Hypertension

Diab

etes

Hypertension &DiabetesCross Roads

• 42% of people with diabetes had normal BP • 56% of people with hypertension had normal glucose tolerance

A prospective cohort study in the United States reported that type 2 diabetes mellitus was almost 2.5 times as likely to develop in subjects with hypertension as in subjects with normal blood pressure

Etiology

DYSLIPIDEMIA DIABETES HYPERTENSION

Increased FFA & triglycerides, Apo B-100 , CETP, MTP,HL, LPL

High leptin,low adiponectin,low vislatin,omentin,vaspin, Increased TNF-alpha & IL-6, high retinol binding protein-4,FFA(via DAG & ceramides

VLDL, triglycerides, sdLDL, HDL, Apo -A1

Incresed FFA, DecreasedNO , RAS activation & aldosterone

Glucotoxicity,lipotoxicity,Inflamtion, endoplasmic reticulum stress

vasoconstriction

leptin, insulin, aldosterone, RAS

Systemic sympathetic activityImpaired Beta cell fuction&

decreases insulin resistance

Genetic FactorsAcquired factorsCentral adiposeEctopic lipid

Environmental factorsDietExercise

Inflammatory oxidative Stress Insulin resistance

Hyperglycemia Dyslipidemia Hyperinsulinemia

RAASVascular dysfunction Sodium

retention SNS

Hypertension

5.5 million people died of stroke in 2002

50% of these were from ASIA (Pakistan, India , China)

HBP- & DM HBP1 HBP2 DM only HBP1 & DM HBP2 &DM0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

11.33

1.9

2.5

3.3

4.09

Rela

tive

risk

of S

trok

e In

cide

nce

Relative risk of Stroke Incidence

<120 120-139 140-159 160-170 180-190 >2000

50

100

150

200

250

300

No daibetesDiabetes

Double jeopardy: Diabetes & Hypertension and Cardiovascular Risk

23.1%

76.8%

0

20

40

60

80

100

Patients with no cardiovascular disease co-morbidities

Patients with diabetes

Hypertension and Diabetes often coexist

Wong et al. Arch Intern Med 2007; 167:2431-2436

0

5

10

Major CV Events

Incidence per 1000 patients

Hypertension without diabetes (n=17,289)Hypertension with diabetes (n=1501)

Stroke CV Mortality

15

CV Mortality

J Hypertens 2001

Co-morbid diabetes significantly increases the risk of CV events in patients with Hypertension:HOT Study

Men Women0

5

10

15

20

25

30

35

40

45HealthyHypertension (treated)DiabetesDiabetes and hypertension

Pre

vale

nce

of m

icro

albu

min

uria

(%

)

Hallan et al. Scand J Urol Nephrol 2003;37:151–158

Hypertension and diabetes are risk factors for microalbuminuria

36.7%

43.5%

0

20

40

60

<140/90 mmHg

Proportion of patients achieving BP goal (%)

13.2%

20.8%

10.5%

14.1%

Hypertension without diabetes (n=3156)Hypertension with diabetes (n=853)

<130/85 mmHg <140/90 mmHg

Cross Road of HTN & DM and likelihood of achieving BP control rates

NA19.733.972%

LAC13.333.0248%

SSA 7.118.6261%

EU17.825.141%

MEC20.152.8263%

India31.779.4251%

China20.842.3204%

A+NZ1.22.065%

Global Projections for the Diabetes Epidemic: 2000-2030 (in millions)

• Obesity (BMI>30): increase by 75% from 2005 to 2015 (from 400 million adults to 700 million)

• Overweight (BMI 25-30): increase by 44% from 2005 to 2015 (from 1.6 billion adults to 2.3 billion)

• Type 2 Diabetes: increase by 114% from 2000 to 2030 (from 171 million to 366 million)

• Hypertension: increase by 56% from 2000 to 2025 (from 1 billion to 1.56 billion)

Hypertension: increase by 56% from 2000 to 2025 (from 1 billion to 1.56 billion)

CV risk factors: becoming more prevalent

Blood Pressure Reduction of 2 mmHg Decreases the Risk of Cardiovascular Events by 7–10%

7% reduction in risk of ischaemic heart disease mortality

10% reduction in risk of stroke mortality

2 mmHg decrease in mean SBP

Lewington et al. Lancet 2002;360:1903–13

JNC 71 ESH-ESC2

Type of hypertension BP goal (mmHg) BP goal (mmHg)

Uncomplicated <140/90 130–139/80–85

Complicated

Diabetes mellitus <130/80 130–139/80–85

Kidney disease <130/80* 130–139/80–85

Other high risk (stroke, myocardial infarction)

<130/80 130–139/80–85

. Chobanian et al. Hypertension 2003;42:1206–522. Mancia et al. Blood Pressure 2009;18:308–47

ESHESC and JNC 7 Guidelines Recommendations for BP Goals

BP ClassificationLifestyle Modification

Initial Drug Therapy

Without Compelling Indication

With Compelling Indication

Normal<120/80 mm Hg

Prehypertension120-139/80-89 mm Hg

Stage 1 hypertension140-159/90-99 mm Hg

Stage 2 hypertension160/100 mm Hg

Encourage

Yes

Yes

Yes

No drug indicated Drug(s) for the compelling indications

Thiazide-type diuretics for most; may consider ACE-I, ARB, BB, CCB, or combination

2-drug combination for most (usually thiazide-type diuretic and ACE-I, ARB, BB, or CCB)

JNC VII: First line recommendations for antihypertensive

RAAS Blockade as Foundation Therapy in Hypertension

ARB Foundation

CCBAlpha

BlockersBeta

Blockers Diuretics Others

RAAS blockade with ARBs can be considered a Foundation of Antihypertensive Therapy

Weir. Am J Hypertens 1998;11:163S-9SDzau. J Hypertens 2005;23 (Suppl. 1): S9-S17

Sica et al. J Clin Hypertens 2002;4:52-7

Rationale for selective angiotensin type 1 receptor blockade

Bradykinin

Inactive fragments

ANGIOTENSIN I

ANGIOTENSIN II

ARB

AT1 RECEPTOR

VasoconstrictionSodium retention

SNS activationInflammation

Growth-promoting effects

AT2 RECEPTOR

VasodilationNatriuresis

Tissue regenerationInhibition of inappropriate

cell growth

Chymase, tPA, ‘Angiotensin II

escape’ACE inhibitor

RAAS

AtherosclerosisVasoconstrictionVascular hypertrophyEndothelial dysfunction

LVHFibrosisRemodeling

GFRProteinuriaAldosterone releaseGlomerular sclerosis

Stroke

Hypertension

Heart failureMyocardial infarction

Renal failure

DEATH

RAAS Plays an Important Role in Organ Damage & CV Outcomes

Willenheimer et al. Eur Heart J 1999;20:997–1008 Dahlöf et al. J Hum Hypertens 1995;9 (Suppl 5):S37–44

Fyhrquist et al. J Hum Hypertens 1995;9 (Suppl 5):S19 –24 Fogo. Am J Kidney Dis 2000;35:179–88

Vasoconstriction

Inflammation

Remodeling

Thrombosis

Stimulates AT1 receptor

Releases endothelin and norepinephrine

Reduces nitric oxide bioactivity and produces peroxynitrite

Activates NADH/NADPH oxidase and produces superoxide anion

Induces expression of MCP-1, VCAM, TNF-α, IL-6

Activates monocytes/macrophages

Stimulates smooth muscle migration, hypertrophy and replication

Induces PDGF, bFGF, IGF-1, TGF-β expression

Stimulates matrix glycoprotein and metalloproteinase production

Stimulates PAI-1 synthesis and alters tPA/PAI-1 ratio

Activates platelets with increased aggregation and adhesion

NADH = nicotinamide adenine dinucleotide; NADPH = nicotinamide adenine dinucleotide phosphate-oxidase; MCP-1 = monocyte chemoattractant protein-1; VCAM = vascular cell adhesion molecule; TNF-α = tumour necrosis factor-α;IL-6 = interleukin-6; PDGF = platelet-derived growth factor; bFGF = basic fibroblast growth factor; IGF-1 = insulin-like growth factor; TGF-β = transforming growth factor-β;tPA = tissue-type plasminogen activator;PAI-1 = plasminogen activator inhibitor type 1

Angiotensin II Has Multiple Vascular Effects

Price DA et al. Am J Hypertens (1999) 12, 348–355

RAAS activity in response to a high-salt diet and recumbent position

‡P<0.01 vs. healthy subjects

Hypertensive Diabetic Patients have an Inappropriately Activated RAAS

Healthy Non-Diabetic DiabeticSubjects Hypertensives Hypertensives

N=23 N=104 N=36

2.0

1.5

1.0

0.5

0

RAAS

Acti

vity

as

mea

sure

d by

PR

A (n

g/m

L/m

in)

‡

Hypertensive Diabetic Patients have an Exaggerated Vascular Response to Ang II

‡P<0.01 vs. healthy subjects* P<0.01 vs. non-diabetic hypertensives

Gordon et al. J Renin Angiotensin Aldosterone Syst. 2000;1(3):252-6

BP response to Ang II infusion

Healthy Non-Diabetic DiabeticSubjects Hypertensives Hypertensives

N=61 N=158 N=38

Chan

ge in

Mea

n Ar

teria

l Pr

essu

re (m

mH

g)

‡ *

‡

15

10

5

0

• ARBs provide a more specific and selective blockade of the effects of angiotensin II than ACE inhibitors

• ARBs tend to have more favourable tolerability than ACE inhibitors

• Unlike ACE inhibitors, ARBs do not disrupt bradykinin degradation, leading to a much lower incidence of treatment-related cough

McClellan KJ, Goa KL. Drugs 1998; 56: 847–869.

Benefits of ARBs over ACE inhibitorsBenefits of ARBs over ACE inhibitors

ARBs are Associated with Higher Adherence Rates Compared with Other Antihypertensive

Drug ClassesA retrospective cohort study analysing claims from

62,754 patients in the German Sickness Fund

Adapted from Höer A et al. J Hum Hypertens 2007;21:744–6

Adhe

renc

e (m

edic

ation

po

sses

sion

ratio

)

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; MPR = medication possession ratioMean (95%CI) MPR: ARBs 0.697 (95%CI:0.686–0.707); ACEIs 0.556 (0.550–0.562); beta-blockers 0.385 (0.382–0.388); CCBs 0.540 (0.531–0.548); diuretics 0.533 (0.525–0.541)

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

ARB ACEI CCB Diuretic Beta blocker

Study nFollow Up

Period BP (mmHG) Drugs Tested Impact on Outcome

Years

UKPDS 510220 Tight Goal150/85 versus

<180/105 Captopril /Atenolol Favors tight control

HOT 187903.8 DSP goal 80 Vs < 90

CCB + others Favors tight control

HOPE,MICRO HOPE 9297 (3577 with

diabetes)

3.5 Mean BP for Both 139/79

Ramipril Vs placebo

Ramipril decreased Mortality & morbidity

ALLHAT42418 (13101) with daibetes)

4.9 Mean BP 146/83 aat baseline Amlodipine Vs Lisinopril

Increased heart failure with amlodipine

ABCD 4705 DSP Intensive 75 Vs moderate

<80-89Nisoldipine Vs enapril

Intensive group decreased death

ACCORD BP 47334.7 SBP <120 Vs <140 Stepped care tp reach

goal

No difference in mortality & morbidity

ON TARGET

25620 (6392 with Diabetes & Organ

Damage)

5.5 141.8±17.4/82.1±10.4 on baseline

Telmesartan Vs Ramipril

Equal in Outcomes but safety is better with telmesartan

Clinical Trials of BP Medication in Patients with Diabetes

ARB CV outcome studies in hypertensive patients – evidence unclear

LIFE• Losartan reduced incidence of stroke compared with atenolol in

patients with severe hypertension and LVH1

• However, atenolol is a weak comparator since it provides poor CV protection compared with all other antihypertensive classes2

VALUE• Valsartan was not better than amlodipine in reducing CV risk in

patients with hypertension and risk factors3

• Valsartan was significantly worse than amlodipine on the incidence of MI

1. Dahlöf B et al. Lancet 2002; 359:995-10032. Carlberg et al. Lancet 2004;364:1684–93. Julius S, et al. Lancet. 2004;363:2022-31

ARB CV outcome studies in hypertensive patients – evidence unclear

ARB CV outcome studies demonstrate effectiveness in heart failure

• Three key ARB trials have shown the effectiveness of ARBs in patients with heart failure

– Val-HeFT and VALIANT showed that valsartan is effective in patients with heart failure or patients with heart failure/LV dysfunction after a recent MI*, respectively

– CHARM showed candesartan is also effective in heart failure

1. Pfeffer MA, et al. N Engl J Med 2003;349:1893-906; 2. Cohn JN, et al. N Engl J Med 2003;345;1667-75;3. Pfeffer MA, et al. Lancet 2003 362: 759–66;

* VALIANT (VALsartan In Acute myocardial iNfarction Trial) was conducted in clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours – 10 days) myocardial infarction.

ARB CV outcome studies demonstrate effectiveness in heart failure

CV High-Risk

Death

Remodelling

Congestive heart failure/secondary stroke

Myocardial infarction and stroke

Hyper-tension

Atherosclerosis and

left ventricular hypertrophy

HFDeath

Ventricular dilation/cognitive dysfunction

Risk factors

LIFEVALUE

ValHeFTVALIANTCHARM

Before ONTARGET, ARB trials had not addressed CV high-risk patients in the middle of the CV continuum

Adapted fromDzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952

Which ARB to reduce events in CV high-risk patients?

• Before ONTARGET, no ARB had been tested for protective

effects in CV high-risk patients

• To demonstrate effectiveness equal to the gold-standard

ramipril, an ARB with the optimal pharmacology was selected

• Telmisartan has a unique pharmacology among ARBs

• This translates to meaningful clinical benefit over other ARBs

Burnier M. JIMR 2009;37(6) e-publish ahead of print

Which ARB to reduce events in CV high-risk patients?

Telmesartan stands out in crowded contest

Burnier M. & Brunner H.R., Lancet 2000;355:637–645; Brunner H.R., J Hum Hypertens 2002;16(Suppl 2):S13–S16; Kakuta H., et al. Int J Clin Pharmacol Res 2005;25:41–46; Wienen W., et al. Br J Pharmacol 1993;110:245-252; Song J.C. & White C.M., Formulary 2001;36:487–499; Asmar,R., Int J Clin Pract. 2006;60:315-320; Israili,Z.H., J Hum.Hypertens. 2000;14 Suppl 1: S73-S86; Benson S.C. et al. Hypertension 2004;43:993–1002

Longest plasma half life Highest receptor affinity

0

20

40

60

80

100

Most lipophilic (high tissue penetration)

0

6

12

18

24Longest Plasma half life

Plas

ma

half

life

(h)

range

Epro-sartan

Lo-sartan

Val-sartan

Olme-sartan

Irbe-sartan

Telmi-sartan

0

50

100

150

200

250 † Active metabolite EXP 3174

Rece

ptor

dis

soci

ation

ha

lf lif

e (m

in)

†

Lo-sartan

Val-sartan

Olme-sartan

Telmi-sartan

Olme-sartan

Val-sartan

Lo-sartan

Irbe-sartan

Epro-sartan

Telmi-sartan

Volu

me

of d

istr

ibuti

on (L

)500

range

PPARg

fold

acti

vatio

n0

5

10

15

20

25

30

EXP 3174(Losartan)

Val-sartan

Olme-sartan

Telmi-sartan

Epro-sartan

Irbe-sartan

Longest half life, Highest receptor affinity, Highest tissue penetration and selective PPARg activation

Highest selective PPARg activation

Highest receptor Affinity

Telmisartan’s unique pharmacology translates to meaningful clinical benefit

0 13 26 39 521300

1500

1700

1900

2100Telmisartan 80 mg (n = 407)

Losartan 100 mg (n = 420)

Week

gMea

n U

PC (m

g/g

crea

tinin

e)

P = 0.03

Bakris et al. Kidney Int 2008; DOI:10.1038/ki.2008.204

n=860

39% more

proteinuria reduction with telmisartan

ONTARGET trial –CV High-Risk patients

n=8,502 Telmisartan 80 mg + Ramipril 10 mg

The ONTARGET Trial in CV High-Risk patients* – the largest ARB outcomes trial

n=8,542 Telmisartan 80 mg

n=8,576 Ramipril 10 mg

5.5 yearsFollow-up at 6 weeks and every 6 months

Teo K, et al. Am Heart J 2004;148:52–61; The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

*Age 55 years at high risk of a CVD event (i.e. with a history of: coronary artery disease, peripheral arterial occlusive disease (PAD), cerebrovascular event, or diabetes mellitus with end-organ damage)

The ONTARGET Trial in CV High-Risk patients* – the largest ARB outcomes trial

Years of follow-up

0.20

0.15

0.05

0.10

00 1 2 3 4 5

Cum

ulati

ve H

azar

d Ra

tio

8,4528,576

8,1778,214

7,7787,832

7,4207,472

7,0517,093

1,6871,703

No. at riskTelmisartanRamipril

TelmisartanRamipril

Telmisartan 80mg reduces devastating CV events similar to ramipril 10mg in CV High-Risk patients

Reduction in composite CV risk (Primary endpoint: cardiovascular mortality, non-fatal myocardial infarction, hospitalisation for congestive heart failure, non-fatal stroke)The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

Reduction in composite CV risk

‡p< 0.01 vs. non-inferiority margin (1.13)

Telmisartan is better tolerated than ramipril (ONTARGET study)

n at riskTelmisartanRamipril

8,5428,576

7,9547,796

7,3847,165

6,9096,681

6,4786,254

Ramipril (10 mg)

Telmisartan (80 mg)

Data on File (Boehringer Ingelheim GmbH)

Years offollow-up0 1 2 3 4 5

0.0

0.1

0.2

0.3

0.4

Cum

ulati

ve h

azar

d ra

tes

(dis

conti

nuati

on fr

om tr

eatm

ent)

(%)

Telmisartan is the only ARB indicated in CV high-risk patients – representing the majority of the patients

typically seen in clinical practice

Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk)

Lo-sartan

Epro-sartan

Irbe-sartan

Olme-sartan

Val-sartan

Telmi-sartan

Hypertension Renal disease with hypertension and T2DM

Prevention of stroke in hypertensive patients with LVH

CV High-Risk Type 2 diabetes with target organ damage Coronary Heart Disease Peripheral Vascular Disease Stroke

Heart Failure (or LV dysfunction)