The Role of Angiotensin Receptor

Blocker in Diabetic Kidney Disease

  Hypertension - or elevated blood pressure - is a serious medical
condition that significantly increases the risks of heart, brain, kidney
and other diseases.
 An estimated 1.28 billion adults aged 30-79 years worldwide have
hypertension, most (two-thirds) living in low- and middle-income
countries

Hypertension is  An estimated 46% of adults with hypertension are unaware that

they have the condition.
major public  Less than half of adults (42%) with hypertension are diagnosed and

health concern treated.

 Approximately 1 in 5 adults (21%) with hypertension have it under
control.
 Hypertension is a major cause of premature death worldwide.
 One of the global targets for noncommunicable diseases is to
reduce the prevalence of hypertension by 33% between 2010 and
2030.
https://www.who.int/news-room/fact-sheets/detail/hypertension#:~:text=An%20estimated%201.13%20billion%20people,cause%20of%20premature%20death%20world
wide.
(Accessed: 26th September 2021)
Hypertension is the number one risk factor
for the global attributable mortality

World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011.
Available at: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/index.html
Prevalensi Indonesia

Prevalensi Hipertensi Menurut Diagnosis atau minum obat, pada

penduduk umur ≥ 18 tahun, 2013-2018
35

30

25

20
%

15

10

0
D/Dokter D/ Atau makan obat Ukur

2013 2018

Riskesdas 2018
Prevalensi Indonesia

Riskesdas 2018
Prevalensi Indonesia

Riskesdas 2018
 THE BURDEN OF UNCONTROLLED
BLOOD PRESSURE

 Not all patients with hypertension are treated

 The majority of patients do not achieve BP goal
 Health burden of uncontrolled BP
 Economic burden of CV disease and
hypertension
Management
Hypertension
 CLASSIFICATION OF OFFICE BLOOD PRESSURE AND DEFINITIONS OF
HYPERTENSION GRADE

2018 ESC/ESH Guideline for the management of arterial hypertension

William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
 WHAT HAS BEEN UPDATED IN ESH 2018?

RECOMMENDATION ESH 2013 ESH 2018

Treatment thresholds High normal BP (130-139/85-89 mmHg). Unless High normal BP (130-139/85-89
the necessary evidence is obtained, it is not mmHg): Drug treatment may be
recommended to initiate antihypertensive drug considered when CV risk is very high
therapy at high-normal BP due to established CVD, especially
More intensive BP CAD
lowering treatment
BP Treatment targets SBP< 140 mmHG was associated with a - 1st Objective: < 140/90 mmHg
25% reduction in - Target ≤ 130 /80 mmHg
major CV events and - Age < 65 yo: SBP 120-129
a 27% reduction in mmHg
BP Target in 65-80 yo SBP 140 – 150 mmHgall cause death SBP 130 – 139 mmHg
BP Target > 80 yo SBP 140 – 150 mmHg SBP 130 -139 mmHg. If tolerated
Initiation of Tx Two-drug combination may be considered In Two drug combination, preferably in a
patients with markedly high baseline BP or at SPC
high CV risk

SBP, Systolic Blood Pressure, BP, Blood Pressure CV, Cardiovascular SPC, Single Pill Combination
2018 ESC/ESH Guideline for the management of arterial hypertension
William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
 SCREENING AND DIAGNOSIS OF HYPERTENSION

2018 ESC/ESH Guideline for the management of arterial hypertension

William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
 INITIATION OF BLOOD PRESSURE LOWERING TREATMENT

2018 ESC/ESH Guideline for the management of arterial hypertension

William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
 Ten year cardiovascular
risk categories (SCORE)

2018 ESC/ESH Guideline for the management

of arterial hypertension
William B, et al. European Heart Journal
(2018) 39, 3021–3104
doi:10.1093/eurheartj/ehy339
 DRUG TREATMENT STRATEGY FOR UNCOMPLICATED HYPERTENSION

2018 ESC/ESH Guideline for the management of arterial hypertension

William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
 DRUG TREATMENT STRATEGY FOR HYPERTENSION & CHRONIC KIDNEY
DISEASE

2018 ESC/ESH Guideline for the management of arterial hypertension

William B, et al. European Heart Journal (2018) 39, 3021–3104 doi:10.1093/eurheartj/ehy339
Selection drug
for special
condition
JNC 8

https://thepafp.org/website/wp-content/uploads/2017/05/2014-JNC-8-Hypertension.pdf. Last access on July 29th 2021.

ANGIOTENSIN
RECEPTOR
BLOCKER
 ROLE OF RAAS INHIBITOR IN INTRARENAL EFFECTS

Kobori H, et al. Curr Pharm Des. 2013 ; 19(17): 3033–3042

The Renin-Angiotensin Aldosterone System (RAAS)

Angiotensinogen Kininogens
Renin Kallikrein
Non-renin
enzymes Angiotensin I Bradykinin
Non-ACE
ACE
enzymes
Angiotensin II Metabolites
ARBs
AT1 AT2
• Vasoconstriction • Aldosterone release • Vasodilation
• Oxidative stress • Vasopressin release • Antiproliferation
• SNS activation • Inhibits renin release • Apoptosis
• Renal Na+ & H2O reabsorption • Antidiuresis/antinatriuresis
• Increased myocardial contractility • Bradykinin production
• Cell growth & proliferation • NO release
 ESSENTIAL
HYPERTENSION
Focus on Irbesartan
 Irbesartan monotherapy VS
Losartan in mild-moderate
hypertension

 Trough SeDBP and SeSBP at Week 8:

Reductions from baseline in trough SeDBP
(primary endpoint), and trough SeSBP were
significantly greater with irbesartan 300 mg Vs
losartan 100 mg (p<0.01 both comparisons by
3.0 and 5.1 mmHg, respectively)
 Throughout the study, the antihypertensive
effect of irbesartan 150 mg did not differ
significantly from that of losartan 100 mg.

Kassler-Taub K. Am J Hypertens 1998;11:445─53.

 Irbesartan monotherapy VS
Valsartan in mild-moderate
hypertension

 Trough diastolic ABP: Compared with

valsartan, irbesartan showed significantly
greater reductions in mean change from
baseline (–6.73 vs –4.84 mmHg, p=0.035).
Mean change from baseline in diastolic ABP at
trough after 8 weeks of treatment with
irbesartan 150 mg and valsartan 80 mg
 Trough systolic ABP: Irbesartan produced
significantly larger decreases vs valsartan (–
11.62 vs –7.5 mmHg, p<0.01)

Mancia G, et al. Blood Press Monit 2002;7:135-42.

 Irbesartan monotherapy VS
Valsartan in mild-moderate
hypertension

 24-hour BP: Irbesartan was also associated with

significantly greater decreases in 24-hour
diastolic ABP (–6.4 vs –4.8 mmHg, p=0.023)
and systolic ABP (–10.2 vs –7.8 mmHg;
p<0.01).

Mancia G, et al. Blood Press Monit 2002;7:135-42.

HYPERTENSION &
KIDNEY DISEASE
Focus on Irbesartan
 Stages in the course
of kidney & cardiovascular disease
Chronic Kidney Cardiovascular
Disease Disease
Kidney
Kidney Failure
Failure (ESRD)
(ESRD) End- Heart
Heart Failure
Failure
Stage

CKD
CKD (
( GFR)
GFR) Progression ASCVD
ASCVD Events
Events

Albuminuria
Albuminuria
CAD,
CAD, LVH,SD
LVH,SD
Proteinuria
Proteinuria Initiation, Injury

Elderly,
Elderly, DM,
DM, HBP
HBP Elderly,
Elderly, DM,
DM, HBP
HBP
At  Risk

NDT
NDT (2001)
(2001) 16
16 (5)
(5) 45-49
45-49
Natural History and Progession of Renal Disease

1. Moosa MR. Important causes of chronic

kidney disease in South Africa. SAMJ.
April 2015, Vol. 105, No. 4
2. Parving H, et al. N Engl J Med. 2001 Sep
20;345(12):870-8. doi:
10.1056/NEJMoa011489
3. Lewis EJ, et al. N Engl J Med 2001;
345:851-860 DOI:
10.1056/NEJMoa011303
4. Viberti G, et al. Circulation
2002;106:672-8
5. Brenner BM, et al. N Engl Med
2001;345:861-9
  Screening & Monitoring
 At least annually, urinary albumin (spot urinary albumin-to-
creatinine ratio) and estimated GFR should be assessed.
 Patients with diabetes and urinary albumin >300mg/g creatinine
and/or an estimated GFR 30-60 mL/min/1.73 m 2 should be
monitored twice annually to guide therapy.
2021 ADA
Recommendations:
Hypertension/Blood  Specific Treatment
Pressure Control  In non pregnant patients with diabetes and hypertension,
either and angiotensin converting enzyme inhibitor (ACEI) or
ARB is recommended for mild (30-299 mg/g) and more severe
elevated urinary albumin to creatinine ratio/UACR (≥ 300
mg/g and/or eGFR < 60 mL/min/1.73 m2).

Standards of Care in Diabetes-2021. Diabetes Care.2021;44(Suppl 1):S151-167

https://care.diabetesjournals.org/content/diacare/suppl/2020/12/09/44.Supplement_1.DC1/
DC_44_S1_final_copyright_stamped.pdf (Accessed: 16th June 2021)
 IRMA-2
Irbesartan in Patients with Early Renal Disease
 Placebo
n = 201

Follow
Irbesartan 150 mg Up 2
Study Design Years
n = 195

Irbesartan 300 mg
590 patients (mean age 58 years) with type 2
n = 194
diabetes, microalbuminuria (albumin
excretion rate 20-200 µg/min), normal renal
function, and hypertension Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.
doi: 10.1056/NEJMoa011489.
 Arterial Blood
Pressure

The average through mean arterial blood pressure

was 103 mmHg in the placebo, 103 mmHg in 150
mg Irbesartan, 102 mmHg in 300 mg Irbesartan (p
= 0.005, compared to placebo) Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.
doi: 10.1056/NEJMoa011489.
 Urinary 24%; P = <0.001

Albumin
Excretion 38%; P = <0.001

Irbesartan reduced the level of urinary

albumin excretion throughout the study
Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.
doi: 10.1056/NEJMoa011489.
 IRBESARTAN SIGNIFICANTLY DELAYS PROGRESSION TO DIABETIC
NEPHROPATHY

Incidence of RR 39%; P = 0.08

Progression to
Diabetic RR 70%; P = <0.001

Nephropathy
10 of 194 patients (5.2%) in 300 mg Irbesartan
and 19 of 195 patients (9.7%) in 150 mg
reached the primary end point compared to
place with 30 of 201 patients (14.9%).
Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.
doi: 10.1056/NEJMoa011489.
 Irbesartan 150 mg Vs
Placebo
39% (P = 0.080)

Reduce risk Irbesartan 300 mg Vs

development of Placebo
clinical proteinuria 70% (P < 0.001)
in 2 years duration
 Regression to normoalbuminuria:
 24% in Irbesartan 150 mg group
 34% in Irbesartan 300 mg group (p = 0.006 vs placebo)

Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.

doi: 10.1056/NEJMoa011489.
  Serious AEs: Recorded in 22.8% of patients in the
placebo group and 15.4% of those in combined
Irbesartan groups (p = 0.02) during treatment and up to 2
weeks after treatment
 Non Fatal Cardiovascular events were slightly more

Safety Profile frequent in the placebo group Vs the Irbesartan 300 mg

group (8.7% cs 4.5%; p=0.11)

 Withdrawal from study therapy: Study medication

was permanently discontinued in 18.9% of the patients in
the placebo group Vs 14.9% of those in the combined
Irbesartan groups (p=0.21)

Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.

doi: 10.1056/NEJMoa011489.
 Irbesartan has proven kidney
protective activity independent of
CONLCUSIO
N its blood pressure lowering action
in patients with type 2 diabetes and
microalbuminuria

Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.

doi: 10.1056/NEJMoa011489.
 IDNT
Irbesartan in Patients with Late Renal Disease Study
Design
 Irbesartan
n = 579
Follow Up
2 Years
Placebo (Average 3
Study Design years)
n = 569

Amlodipine
1715 patients (mean age 59 years) with type n = 567
2 diabetes, nephropathy (proteinuria ≥ 900
mg/d) and hypertension
Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
 Arterial Blood
Pressure

Irbesartan produces a consistent blood

pressure response
Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
 IRBESARTAN REDUCES THE PROGESSION OF DIABETIC NEPHROPATHY
(COMBINED ENDPOINT)

Primary end
point

Irbesartan reduces the progession of diabetic

nephropathy (combined endpoint: Time to
doubling serum creatinine, ESRD, or death)
Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
 Irbesartan Vs Amlodipine

23% (P = 0.006)
Irbesartan reduce
the progression Irbesartan Vs Control

of diabetic 20% (P = 0.02)

nephropathy
Amlodipine Vs Control

P = NS
Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
 Time to renal end
point (Doubling of
serum creatinine)

 Irbesartan Vs Amlodipine: RR = 37%, P = < 0.001

 Irbesartan Vs Control: RR = 33%, P = 0.003
 Amlodipine Vs Placebo: RR = -6%, P = 0.60 Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
  Irbesartan reduced the incidence of the
primary composite endpoint of a doubling of
serum creatinine, ESRD or death by 23% Vs
Amlodipine (p= 0.006) and 20% vs Placebo
(P=0.02)

CONLCUSIO  Risk of a doubling of the serum creatinine

concentration was reduced 33% in the
N irbesartan group compared to 10% with placebo
(37% Vs Amlodipine)
 These benefits were above and beyond those
attributable to blood pressure reduction alone

Lewis EJ, et al. N Engl J Med 2001; 345:851-860

DOI: 10.1056/NEJMoa011303
 IRBESARTAN DELAYS PROGRESSION OF NEPHROPATHY AS MEASURED BY
ESTIMATED GLOMERULAR FILTRATION RATE

Post Hoc
Analysis IDNT

In long term, Irbesartan significantly

slowed the rate of eGFR. eGFR decline
(mL/min/m2/year):
• Irbesartan: - 2.34
• Amlodipine: - 3.76
• Placebo: -3.52 Evans M, et al. Nephrol Dial Transplant (2012) 27: 2255–2263
doi: 10.1093/ndt/gfr696
  Irbesartan produced a rapid and sustained
proteinuria reduction
 The long-term efficacy of Irbesartan was
independent of change in blood pressure
 Irbesartan has been shown to reduce endothelial
dysfunction, oxidative stress and inflammation. In
CONLCUSIO addition, RAAS blockade decreases collagen
N formation and improves kidney oxygenation
 Irbesartan significantly slowed the long term
rate of decline in eGFR compared to non
RAAS inhibitor, resulting in delayed
progression towards ESRD by 33%
Lewis EJ, et al. N Engl J Med 2001; 345:851-860
DOI: 10.1056/NEJMoa011303
THANK YOU
Prevalensi Indonesia

Riskesdas 2018
Prevalensi Indonesia

Riskesdas 2018
 The Continuum
Of Disease

Sarnak MJ, et al. Am J Kidney Dis. 2000 Apr;35(4 Suppl 1):S117-31.

doi: 10.1016/s0272-6386(00)70239-3.
The decline in
creatinine
clearance

Parving H, et al. N Engl J Med. 2001 Sep 20;345(12):870-8.

doi: 10.1056/NEJMoa011489.
 Mechanism
Action of ARB

https://www.racgp.org.au/afp/2013/september/aceis-for-cardiovascular-risk-reduction/ (Accessed: 25th August 2020)