FARMAKOTERAPI

ANTIHIPERTENSI
Jimmy Posangi
Bagian Farmakologi dan Terapi
FAKULTAS KEDOKTERAN UNIVERSITAS SAM RATULANGI
MANADO 24 Mei 2012

Klasifikasi obat antihipertensi

A. Golongan Diuretika

B. Golongan Adrenergik

C. Golongan Vasodilator

D. Golongan Sistim Renin-Angiotensin

E. Golongan Penghambat Kalsium

Sites of action

Diuretics
MANNITOL
Proximal
Convulated Tubule

65%

FUROSEMIDE
Thick Segment
Ascending
Limb of Henles
Loop

THIAZIDES
Early Distal
Convulated Tubule

10%
20%

Spironolactone,
Triamterene

1%-5%

Late Distal
Convulated
Tubule and
Collecting Duct
(Distal Nephron)

Neurotransmitter

Effectors
cell

Cell Signaling

- Blocker

Noradrenaline

adrenergic

Propranolol
Effectors
cell

 - Blocker

Noradrenaline

adrenergic

Prazosin
Effectors
cell

 2 - Agonist

Noradrenaline

adrenergic

Clonidine
Effectors
cell

Ganglia Blocker

Acetylcholine
Trimethaphan
cholinergic

adrenergic
Sympathetic
Ganglia

Sympatholitic

Reserpin

Effectors
cell

Acetylcholine
Endothel Cells
Ca 2+ Calmodulin

NO SYNTHASE
Arginine + O2

Citrulline + NO

NO

Smooth Muscle Cells

Fe

Guanylate
Cyclase
GTP

cGMP

Relaxation

Vasodilator
Nitroprusside
Extracellular

NO
Smooth Muscle Cells
Fe

Guanylate
Cyclase
GTP

cGMP

Relaxation

ACE - inhibitor dan Renin Inhibitor

Angiotensinogen

propranolol
Enalkiren

+ Renin
X

Angiotensin I
Captopril
Quinapril, etc

Remikiren
Bradykinine

ACE

Angiotensin II

Peptide inaktif

Angiotensin II Blocker

Angiotensin II

Losartan
Effectors
cell

Physiology of Calcium Channel

MEMBRANE

Endoplasmic reticulum
Voltage-gated
Ca2+ Channel

Ca 2+

Ca 2+
calmodulin
Myosin
light-chain kinase
Phosphorilation

Extra cell

Cytosol

Actin and myosin

interaction

Calcium Channel Blocker

MEMBRANE
NIFEDIPINE

Endoplasmic reticulum

Ca2+
calmodulin

Voltage-gated
Ca2+ Channel

Extra cell

Cytosol

BENEFIT-RISK OBAT ANTIHIPERTENSI

Golongan Obat
Antihipertensi
dan Prototip Obat

Diuretik
TIAZID

Keunggulan

Murah,
tak ada rebound
phenomena

Efek Samping
dan Kerugian
Lain
K+ depletion.
Mg++ dan Ca++
naik .
Glukosa dan
LDL naik.
Perlu replacement
K+.

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat

Bloker Beta

PROPANOLOL

Keunggulan

Efek Samping
dan Kerugian
Lain

Efektif, frekuensi
jantung turun.
Menentramkan,
renin turun.

Bronhospasme.
Kongesti nasal.
Kelelahan.
Bradikardi.
Gangguan hantaran
A-V, Raynauds
phenomena.
Impotensi, inhibisi
glukoneogenesis.
rebound +

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat

Bloker Alfa
PRAZOSIN

Keunggulan

Efek Samping
dan Kerugian
Lain

Hipotensi
Efek vasodilator ortostatik.
Terpilih bagi
Adanya toleransi
hipertensi + gagal bila pakai lama.
Palpitasi, mulut
jantung kongestif. kering, diare.
Memperbaiki
Kongesti nasal.
rasio HDL/LDL. Disfungsi seksual

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat

2-Agonis
KLONIDIN

Keunggulan

Efek Samping dan

Kerugian Lain

Ortostatik efek
kurang.
Baik untuk
hipertensi resisten,
dikombinasi dgn
diuretika dan
dilator

Ada rebound
effect
Sedasi, mulut
kering.
Disfungsi seksual.
Mual, konstipasi.

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat

Penghambat
adrenergik
RESERPIN

Keunggulan

Efek Samping dan

Kerugian Lain

Ortostatik kurang.
Murah.
Efek hanya berobah
sedikit walau pasien
tak patuh.
Masa kerja panjang.
Rebound effect
relatif tak ada.

Efek samping
depresi.
Dapat terjadi ulkus
peptikum.
Kongesti nasal.
Disfungsi seksual.
Dampak EkstraPiramidal.
Ginekomasti.

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat
Vasodilator
arteriole
HIDRALAZIN

Keunggulan

Efek Samping dan

Kerugian Lain

Sakit kepala.
Dipakai pada krisis
Tahikardi.
hipertensi dan
GIT intolerance.
Eklamsi

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi
dan Prototip Obat

Ca-channel
blocker
NIFEDIPIN

Keunggulan

Efek Samping dan

Kerugian Lain

Fungsi seksual
relatif normal.
Baik pakai pada
usia lanjut.
Boleh dipakai pada
Emergency.

Sakit kepala.
Edema, konstipasi.
Palpitasi dan
Bradikardi.

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)

Golongan Obat
Antihipertensi dan
Prototip Obat

ACE-inhibitor
KAPTOPRIL

Keunggulan

Efek Samping dan

Kerugian Lain

Efektif bagi
hipertensi berat.
Fungsi seks relatif
normal.
Dapat dipakai pada
gangguan ginjal.

Skin rash, alergi ,

batuk.
Gangguan
Pengecap (disgeusia)
Mual,muntah,diare
sakit kepala.

OBAT BAGI KEDARURATAN HIPERTENSI

Obat/
Golongan
Nitroprusid
Vasodilator
Diazoksid
Vasodilator
Trimetafan
Bloker
ganglion

Dosis/cara
0,5-10
gr/kgbb/
mnt i.v
drips

Mula
Kerja

Lama
Kerja

Bebera- 3-5 menit

pa detik

Keterangan

Beri bersama
Blocker
bila
ao.disekans

15-30
1-5
mg/mnt-300 menit
mg i.v drips

4-12 jam

Bahaya pada
penyakit
koroner

1-5 mg/mnt
i.v

10 menit

Baik pada ao.

Disekans

1-3
menit

OBAT BAGI KEDARURATAN HIPERTENSI (Samb.)

Obat/
Golongan

Dosis/cara

Mula
Kerja

Lama
Kerja

Keterangan

Esmolol
Blocker

500 gr/kg 1-2

menit
load + 25200 gr/mnt
maintenance
i.v

Labetalol
&
blockers

20-300
mg/10 mnt
parenteral

5 menit 3-6 jam

Bahaya pada
asma & CHF

Hidralazin
Vasodilator

5-20 mg
i.v/i.m

10-30
menit

2-6 jam

Bahaya pada
p. Koroner

15
menit

6 jam

Baik +
diuretik

Enalaprilat

1,25 mg/6
ACE inhibitor jam i.m

10-30 mnt Bahaya pada

asma dan
CHF

OBAT BAGI KEDARURATAN HIPERTENSI (Samb.)

Obat/
Golongan
Furosemide

Dosis/cara

Mula
Kerja

Lama
Kerja

Keterangan

10-80 mg
i.v/i.m

15
menit

4 jam

Hipokalemi

10 mg
ulangi tiap
30 mnt/oral

15
menit

2-6 jam

Awas angina

0,2 mg lalu -1
+ 0,1-0,8
jam
Simpatolitik mg/jam/oral

6-8 jam

Awas rebound

Kaptopril

4-6 jam

Hipotensi
berlebihan

Diuretik
Nifedipin
Ca-blocker
Klonidin

ACE inhibitor

6,25-25 mg
oral

15-30
menit

Strategi Pengobatan
Hipertensi The stepped care

Tahap 1. Terapi satu obat

Tahap 2. Terapi dua obat

Tahap 3. Terapi tiga obat

Tahap 4. Terapi empat obat

Stepped care

Kaku

Kurang akomodatif terhadap:

- Respons individu
- Reaksi individu

Individualized approach
(mempertimbangkan)

Umur

Ras

Penyakit penyerta

Obat lain yang dipakai

Gaya hidup

Status sosial-ekonomi

Kesimpulan
- Mengurangi mortalitas dan morbiditas
- Aksi farmakologi: volume, arus, dinding
- Penggunaan seyogianya:
rasional
efektif
aman
ekonomis

TERIMA KASIH

Tekanan Darah Tinggi dan Stroke

Prof. dr. Iwan Darmansjah, Ahli Farmakologi Klinik
Mengapa banyak orang meninggal karena stroke dalam usia yang relatif muda di Indonesia? Salah satu penyebab ialah
karena banyak penderita tekanan darah tinggi yang tidak diobati/diturunkan tekanan darahnya. Tekanan darah tinggi
memang tidak bisa dirasakan dengan sakit kepala. Sebagian besar masih berjalan tanpa keluhan apa-apa. Tekanan
darah tinggi hanya bisa dipastika dengan alat yang disebut tensi-meter. Normal ialah tekanan darah yang tidak lebih
tinggi dari 120 mm air raksa sistolik (tanpa mempersoalkan tekanan diastolik. Kriteria ini berlaku bila diperiksa dalam
keadaan istirahat atau setelah duduk sekitar 7-10 menit. Inipun ada caracara pemeriksaan yang standard. Semakin
melebihi tekanan sistolik 120, semakin tinggi hipertensinya dan semakin besar risiko terkena stroke. Stroke bisa
disebabkan oleh perdarahan atau penggumpalan darah. Sekitar 50% penderita stroke berakibat kematian, karena itu
tekanan darah tinggi harus diobati dan dijaga berat badannya,. Pengobatan bertujuan untuk memperkecil risiko stroke.
Semakin tinggi tekanan darah, semakin besar risiko ini, karena itu pengobatan ialah sepanjang umurnya pasien.
Pengobatan juga memerlukan pengertian pasien dengan informasi. Sayangnya tidak banyak dokter yang memberi
informasi. Tidak banyak dokter mengerti benar cara mengobati penyakit TD tinggi. Di bawah ini saya jelaskan dg
sederhana: Kita memiliki sekitar 200 jenis obat antihipertensi dalam nama generik. Sebagian besar sudah memenuhi
syarat utk diberi hanya satu kali (pagi) sehari. Hal ini penting karena obat harus bisa bertahan efeknya sepanjang 24
jam. Masih ada yang lama kerjanya hanya 5-6 jam , dan obat jenis ini harus diberi 2-3 kali sehari. Jenis terakhir ini
sebaiknya tidak dipakai, karena tidak praktis. Prosedur: umum: hari pertama dimulai dengan memakai 1 jenis obat
yang terpilih oleh dokter, dan diteruskan sedikitnya 1-2 mg untuk dicek apakah TD turun. Bila tidak turun, maka
ditambah dg obat ke dua yang cocok, dan TD-nya dicek lagi setiap hari. Bila efeknya memuaskan , maka 2 obat
diteruskan bersamaan selama 1-2 mg dan seterusnya bila penurunan TD cukup baik. Bila di mg ketiga TD naik lagi,
maka boleh ditambah obat ke tiga. Bila hasilnya memuaskan, maka 2 atau 3 obat itu diteruskan sambil observasi. Ini
merupakan prosedur yang, bila TD bandel, boleh dikombinasi sampai maksimal 4 obat (semua dengan dosis kecil dan
tidak dibenarkan memakai dosis besar. Cara ini bertujuan supaya kita tidak menaikkan dosis obat sebelumnya dan
mengharapkan terjadi sinergisme dan menjaga dosis tetap rendah, sehingga lebih aman. Pilihan campuran diserahkan
dokter yang menilai. Semua obat biasanya diberi bersamaan pagi hari. Mengontrol TD dg cara demikian lebih baik
daripada terserang stroke. Dengan metode ini, sebagian besar pasien biasanya tertolong dengan 2-3 kombinasi. Juga
dalam perjalanan pengobatan, bisa saja salah satu obat dikurangi, sambil dicek. Juga pasien terlindungi oleh risiko
stroke.

Pressure
Lowering Effect
of ARBs:
Are They All the
Same?
Budi Yuli Setianto, MD, FIHA, FINASIM
Department of Cardiology and Vascular Medicine Faculty of Medicine Gadjah
Mada University Sardjito Hospital, Yogyakarta

Hypertension
More Than Just High BP
A complex syndrome in which neurohumoral and
metabolic abnormalities influence development
and progression of vascular disease and clinical
events
A complex inherited syndrome of cardiovascular risk
factors

Hypertension Syndrome

Giles,TD, JCI Suppl,2005

Obesity

Decreased
Arterial
Compliance

Endothelial
Dysfunction

High
HighBlood
BloodPressure
PressureisisaaLate
Late
Manifestation
of
the
Hypertension
Manifestation
of
the
Hypertension
Hypertension
Syndrome
Syndrome
Abnormal Lipid
Metabolism

Accelerated
Atherogenesis

Abnormal
Glucose
Metabolism

Neurohormonal
Dysfunction

LV Hypertrophy
Renal-Function
Neutel JM et all, Am J Hypertens, 1999; 12:215-223
and Dysfunction
Changes
Neutel JM et all, Am J Hypertens, 1999; 12:215-223
Abnormal
Blood-Clotting
Insulin
Mechanism
Metabolism
Changes

Kannel WB. JAMA..

Weber MA et al. J Hum Hypertens. 1991;5:417-423.
Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5. 1996;275:1571-1576

DIABETES and HEART DISEASE

Framingham

Study

Diabetes Mellitus doubles risk of Cardiovascular disease

in
men and triples risk in women

Multiple

Risk Factor Intervention Trial (MRFIT)

Cardiovascular

death three times higher in diabetic men

as compared to men without diabetes

Cardiovascular

death five times higher in diabetic men

as compared to men without diabetes when optimal risk
factor status is obtained

Primary defects in type 2 diabetes

Primary defects in type 2 diabetes1-3

GLUCOSE TOXICITY

-cell
-cell
dysfunction
dysfunction

Insulin signalling
signalling
Insulin
defect
defect

Loss of
of early
early phase
phase
Loss
insulin release
release
insulin

Insulin resistance
resistance
Insulin

Postprandial
Postprandial
glucose spikes
spikes
glucose

Increased basal
basal
Increased
glucose levels
levels
glucose

The development of type

2 diabetes is the result
of a combination of cell dysfunction and
insulin resistance

Hyperglycaemia
Hyperglycaemia
Adapted from Lebovitz, Ward and Yki-Jrvinen
1 Lebovitz HE. Diab Rev 1999; 7: 139-153. 2 Ward W, et al. Diab Care 1984; 7: 491-502. 3 Yki-Jarvinen H. Endocrine Revs 1992; 13: 415-431.

Antihypertensive Agent
Blood pressure
lowering effect

Non blood pressure

lowering effect
insulin sensitivity
microalbuminuria
endothelial dysfunction
arterial compliance
LV hypertrophy and
dysfunction
atherogenesis

ANTIHYPERTENSIVE TREATMENT IN DIABETICS

Goal BP should be 130/80 mm Hg and treatment may be
started already when BP is in the high normal range.
To lower BP, all effective and well tolerated drugs can be used.
A combination of two or more drugs is frequently needed.
A blocker of the RAAS should be a regular component of
combination treatment and the one preferred when
monotherapy is sufficient.
Microalbuminuria should prompt the use of AHD treatment
also when initial BP is in the high normal range. Blockers of
the RAAS have a pronounced antiproteinuric effect
ESC and ESH Guidelines 2007

Persistence with therapy after 1 year (%)

Persistence with BP-lowering

theraphy after 1 year UK data
(sample n= 5,505,875)

What are the main mechanism responsible for the

anti-diabetic effects of ACEIs and ARBs ?

ACEIs
ALL inhibit the renin-angiotensin
system

+
ALL

bradykinin

ARBs
ALL inhibit the
renin-angiotensin
system
+
Some PPAR
(Telmisartan)

Angiotensin II Formation
Angiotensinogen
Renin

Angiotensin I
ACE

CAGE
Cathepsin G
Chymase

t-PA
Cathepsin G
Tonin

Angiotensin II
Angiotensin II Receptors
Dzau VJ et al. J Hypertens. 1993;11(suppl):S13-S18.

Angiotensin
II

ARBs

Expressed
Expressed only
only after
after injury
injury

Constantly
Constantly expressed
expressed

AT11 receptor
Non-Hemodynamic
Non-Hemodynamic
Stress
Stress oxidative
oxidative //

inflammation
inflammation
TGF
TGF -- &
& ECM
ECM
PAI
PAI 11

Aldosterone
Aldosterone
Symphatic
Symphatic Activity
Activity

Hemodynamic
Hemodynamic

Vasocontriction
Vasocontriction
RBF
RBF
P
P gc
gc

AT22 receptor

Vasodilatation
Vasodilatation
Natriuresis
Natriuresis
Growth
Growth Inhibition
Inhibition

Wiecek
Wiecek A
A et
et al.
al. NDT
NDT 2003;18(suppl
2003;18(suppl 5):v16-v20
5):v16-v20

Telmisartan 80mg is as protective as Ramipril 10mg

in terms of CV protection
Reduction in composite CV risk

Composite CV risk = cardiovascular mortality, non-fatal myocardial infarction, hospitalisation for

congestive heart failure, non-fatal stroke

The ONTARGET Investigators. N Engl J Med 2008;358:15471559

Telmisartan 80mg added to Ramipril 10mg

:
as effective as Ramipril alone
Reduction in composite CV risk

Composite CV risk = cardiovascular mortality, non-fatal myocardial infarction,

hospitalisation for congestive heart failure, non-fatal stroke
The ONTARGET Investigators. N Engl J Med 2008;358:15471559

Telmisartan is superior to Ramipril

in 24 hour ABPM reduction
DBP change from baseline
(mmHg)
Time after closing (h)
PRISMA II

Is there a differences between

ARBs on non blood pressure
lowering effect?

SOME ARB POSSES PARTIAL AGONIST PPAR ACTIVITY, DUE TO

STRUCTURAL SIMILARITY WITH THE THIAZOLIDINEDIONES
(FULL AGONIST PPAR ACTIVITY)

TELMISARTAN > IRBESARTAN > LOSARTAN

METABOLITES

Scheen AJ. Diabetes Metab. 2004;30:498-505

Telmisartan has a different structure

which explains its unique pharmacology

Chemical structures of the most widely used angiotensin receptor blockers (ARBs), illustrating the
unique nature of telmisartan. The circle encloses the biphenyl tetrazole moiety that is common to
losartan and its related ARBs.

ARBs Comparison of
pharmacological properties
Olmesartan

Losartan

Candesartan

Irbesartan

Telmisartan

Eprosartan

Valsartan

Yes

Yes

Yes

No

No

No

No

Noncompetitive

Competitive
(active
metabolite
is noncompetitive

Noncompetitive

Noncompetitive

Noncompetitive

Competitive

Noncompetitive

AT1:AT2
affinity

12,500

1,000

>10,000

8,500

>3,000

1,000

20,000

t1/2 (hours)

10-15

6-9

11-15

24

5-9

1-2

3-4

3-4

1.5-2

0.5-1

1-2

2-4

Vd (L)

16-29

34

0.1 L/kg

53-93

500

~13

~23

Bioavailability (%)

25.6

~33

14

60-80

50

13

23

Prodrug
Receptor
antagonism

Tmax (hours)

56

ARBs Comparison of pharmacological properties

(cont.)
Olmesartan

Losartan

Candesarta

Irbesartan

Telmisartan

Eprosartan

Valsartan

Faecal
elimination
(%)

50-65

60

67

80

98

90

83

Urinary
elimination
(%)

35-50

35

33

20

<1

13

CYP450
metabolism

No

Yes
CYP 3A4

No

Yes
CYP 2C9

No

No

No

Drug
interactions

No

Rifampin,
fluconazo
le

No

No

Digoxin

No

No

Effect of
food
( AUC%)

None

10

None

None

6-20

25

40-50

Dosing
frequency

od

od/bid

od/bid

od

od

od/bid

od

57

Peroxisome Proliferator-Activated
Receptors (PPARs)
Members of nuclear receptor superfamily
Transcription factors that regulate gene expression in
response to certain endogenous and exogenous ligands
Acts as a central transcriptional mediators in the regulation
of several important metabolic processes that influence :
adipogenesis, insulin sensitivity, glucose homeostasis,
lipid metabolism, vascular endothelial function,
inflammation, atherosclerosis progression, and
ultimately cardio-reno-vascular risk

Mudaliar S, Henry RR. Curr. Opin. Endocrinol. Diab. 2002;9:285-302

Location and Function of PPAR

Superfamily
PPAR subtype
Distribution
Fisiology function
PPAR

Liver
Kidney
Heart
GITs
Skeletal muscle
Fat tissue
Retina

Peroxisome proliferation
Lipid Oxidation
Gluconeogenesis

PPAR

All tissue
except smooth muscle

Fat Differentiation

PPAR

Fat tissue
Skeletal muscle
Liver
Heart
Kidney
Endothel
VSMC

Glucose uptake
Gluconeogenesis
Glycogenesis & Glycolysis
Fatty acids uptake
Lipogenesis
Fat Differentiation

MECHANISM OF ACTION OF PPAR AGONIST

L TissuesPPAR Ligands
Target
- Natural: Long chain FA
Fat, Liver;
SkeletalThiazolidinediones
muscle; Heart
- Synthetic:
Endothelial cells; Kidney, VSMCs

L
L

RA

PPAR

RXR

Target Genes
FA binding protein
FA transport protein
Acyl CoA oxidase
PAI-1; VCAM; IL-6

Target gene
transcription

DNA

Response element
Target gene

MECHANISM OF ACTION OF PPAR AGONIST

Regulation of
Target
Gene Transcription

RA

PPAR

RXR

Response element
DNA response
element receptor

Glucose Transporters
TNF -

Target gene
transcription
Benificial effect on
Hyperglycemia
Hyperinsulinemia
Dyslipidemia
Inflammation
Endothelial Dysfunction

Target gene

DNA

Dual ARB - PPAR Ligand

PPAR
Modulation

NF-B
TNF-
PAI-1
Fibrinogen

CRP
IL-6
VCAM
NO

Dyslipidemia
Adiponectin
Insulinemia
Insulin sensitivity
Leptin
ACC2
Weight gain

Blood pressure
Tissue fibrosis
Tissue inflammation
Cell proliferation
Oxidative stress
Endothelial dysfunction
SNS activity

Steatohepatitis

Cardiac function
Cardiomyopathy

Atherosclerosis
Atherogenesis

AT1-R Blockade
AT2-R Activation
Ang - II

Glomerulosclerosis
Neuroregulation

Islet function

Ability of different ARBs to Activate PPAR

Fold
activation

30

20

10

Candesartan Olmesartan Eprosartan

Valsartan

Losartan
Irbesartan
Metabolite

Telmisartan

10 micromolar
Benson SC et al. Hypertension 2004;43:993-1002

Plasma half-life of
ARBs

Plasma half life (h)

Kalkuta et al. Int J Clin Pharmacol Res 2005;25:41-46

Effects of telmisartan and losartan on

measures of glycaemia and insulin resistance
in 40 patients with metabolic syndrome

Change from baseline (%)

FPG

FPI

HOMA-IR

HbA1c

0
-5
-10

P < 0.05

P < 0.05

P < 0.06

-15
-20

Losartan

-25

Telmisartan

-30

P < 0.05
P-values indicate telmisartan-losartan comparison

FPG = fasting plasma glucose, FPI = fasting plasma insulin, HOMA-IR =

homeostatic model assessment insulin resistance, HbA1c = glycosylated
haemoglobin.

Vitale C, et al. Cardiovasc.Diabetol. 2005;4:6

Conclusion: In hypertensive patients with IGT telmisartan

compared to losartan improved endothelial function and
insulin resistance
independently, supporting the hypothesis that
glucometabolic and vascular insulin resistance are
differentially regulated.
Perl S et al. Int J Cardiol 2008.

% change compared to baseline

Changes in Glucose, Insulin, and Insulin Resistance From

Baseline in Patients with the Hypertension Metabolic
Syndrome
Glucose

4
2
0
-2
-4
-6
-8

Losartan

Insulin

HOMA Index
Insulin Resistance
Losartan

Losartan

Telmisartan

p<0.06
Telmisartan

Telmisartan

p<0.05

p<0.05
(G. Rosano et al., VII Forum on the Renin-Angiotensin System, 2004)

Do ARBs also reduce the risk of new onset

diabetes in patients without heart failure?
Randomized, double blind, placebo controlled trials :

SCOPE (candesartan)

PROFESS (telmisartan)

TRANSCEND (telmisartan)

Rate of new diabetes

Candesartan Did Not Significantly Reduce the

Risk of New Onset Diabetes in the SCOPE Trial
Odds ratio = 0.8
95%, CI = 0.60
1.07
P=ns

Other drugs: 33% diuretics

17% B-Blocker
18% CCB

44% diuretics
26% B-Blocker
88% CCB

Meta-Analysis of the Effects of Telmisartan on New Onset

Diabetes in PRoFESS and TRANCEND Trials
(comparisons againts placebo groups)

Significant anti diabetic effect of telmisartan vs placebo

16% risk reduction for diabetes (3% - 28%)

Telmisartan improves glucose metabolism more

than Irbesartan in diabetics with metabolic
syndrome

Study duration = 12 months

All patients taking rosiglitzone 4
mg/d

G. DeRosa et al, Hypertension Research, 2006

Telmisartan is a Bridge to the future for

Next Generation ARBs that Do More than just
Block Angiotensin Receptors

1st Generation
ARBs
AT1 Receptor
Blockade

2nd Generation
ARB

Telmisartan
~ Metabosartan

3rd Generation
ARBs
More than AT1
Blockade

Next Generation ARBs on Horizon

Molecule
name
K-868 (Kyowa Kirin)
PF-03838135 (Pfizer)
Azilsartan (Takeda)
ARNI (Theravance)
LCZ-696 (Novartis)
PS433540 (Ligand)
WB1106

Stage of
development

Additional action
beyond AT1
blockade

Preclinical

PPAR partial agonism

Preclinical

PPAR partial agonism

Phase III

PPAR gene expression

Preclinical

Natriuretic peptides

Phase II /III

Natriuretic peptides

Phase IIb

Block endothelin receptors

Preclinical

Nitric oxide donor

Preclinical

Nitric oxide donor

3-[(nitrooxy)methyl]
benzoate ester of losartan

TW Kurtz and U Klein, Hypertension Research, 2009

SUMMARY
1) The risk for developing type 2 diabetes is doubled in patients with
hypertension and is increased 5 9 fold by the metabolic syndrome
2) Telmisartan is a dual ARB / selective PPAR modulator is a

metabosartan that blocks AT1 receptors and activates PPAR,

a known therapeutic target for the hypertension & diabetes

3) Telmisartan

Reduce the risk for new onset diabetes

Is the only ARB approved for reducing CV morbidity in patients

with type 2 diabetes

Should be considered as first choice ARB in the metabolic

syndrome

Represent a bridge to the future for next generation ARBs