NNικόλαοςικόλαοςΚουρεµένοςΚουρεµένος↑LP contact with vessel wall...

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Υπέρταση και ∆ιαβήτης Nικόλαος ικόλαος Κουρεμένος Κουρεμένος MD, PhD, FESH Cardiology Dep. Asklepeion Hospital, Athens, Greece

Transcript of NNικόλαοςικόλαοςΚουρεµένοςΚουρεµένος↑LP contact with vessel wall...

Υπέρταση και ∆ιαβήτης

NNικόλαοςικόλαος ΚουρεµένοςΚουρεµένος

MD, PhD, FESH

Cardiology Dep. Asklepeion Hospital, Athens, Greece

CV Prevention in EURO ASPIRE I, II & III

I II III

58.1 58.3

60.9

94.5

76.7

Kotseva, Lancet, 2009, 373, 923-940

Smokers

p = NS

Obesity

p < 0.001Hypertension

p = NS

Diabetes

p = 0.004

Raised TC

2525252525252525

20.3

21.2

18.2

25

32.6

38

2525252525252525

17.4 20.1

28

2525252525252525

46.8

Hypertension Dyslipidemia RAASDiabetes Heart Rate

Smoking Obesity SNS Hyperhomocysteinemiaa CRP Uric Acid

ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION

Monocytes

MacrophagesMacrophages

EndotheliumEndothelium

VasoconstrictionVasoconstrictionCell adhesion Cell adhesion

and/or infiltrationand/or infiltrationProliferationProliferation Lipid accumulationLipid accumulation

Ischemic Heart DiseaseIschemic Heart Disease Cerebrovascular DiseaseCerebrovascular Disease Peripheral Vascular DiseasePeripheral Vascular Disease

MacrophagesMacrophages

↑ Endothelial Permeability

↑ LP contact with vessel wall

↑ Adhesion to endothelial cells

↑ O·2 generation

↑ Cytokines

↑ Uptake of oxidized LDL

↑ Tissue Factor

↑ PAI-1

↑ ICAM, VCAM

↑ MCP-1

↓ eNOS

↓ Prostacyclin

↑ Catecholamines

↑ Angiotensin II

↑ VSMC Proliferation

Manolis AJ. ESH Textbook 2008

Diabetic

Retinopathy

Leading cause

of blindness

in adults Cardiovascular

Stroke

2- to 4-fold increase in cardiovascular

mortality and stroke5

Type 2 diabetes is associated with serious

complications

in adults

Diabetic

Nephropathy

Leading cause of

end-stage renal disease3,4

Cardiovascular

Disease

Diabetic

Neuropathy

Leading cause of

non-traumatic lower

extremity amputations7,8

8/10 individuals with

diabetes die from CV

events6

Hypertensive Patients with DM

Are at Increased CV Risk

Men with DM (n=5163)MRFIT, N=347,976

250

CVD Deaths/10,000

Years

200

300 Men without DM (n=342,815)

CV = Cardiovascular

Stanler J et al. Diabetes Care. 1993;16: 434-444

50

150

<120 120-139 140-159 160-179

Systolic BP (mmHg)

CVD Deaths/10,000

Person-Years

0

100

180-199 ≥200

Risk Factor for the Development of AF

38-year follow-up of the Framingham studyadjusted odds ratio

3

4

Risk factors

Age-adjusted odds ratio

Cigarettes

1

2

0

Diabetes ECG LVH Hypertension BMI Alcohol

ESH/ESC GuidelinesStratification of CV Risk in Four Categories

High

added risk

Moderate

added risk

Low Low

added riskadded risk

Other Risk Factors,

OD

or Disease

Grade 1 HT

SBP 140-159

or DBP 90-99

Grade 2 HT

SBP 160-179

or DBP 100-109

Grade 3 HT

SBP ≥ 180

or DBP ≥ 110

Average

risk

Average

risk

Normal

SBP 120-129

or DBP 80-84

High Normal

SBP 130-139

or DBP 85-89

No other risk factors Low

added risk

Very high

added risk

Very high

added risk

Very high

added risk

Very high

added risk

Very high

added risk

High

added riskHigh

added risk

Moderate

added risk

Moderate

added risk

3 or more Risk Factors,

MS, OD or Diabetes

Very high

added risk

Very high Very high

added riskadded risk

High

added riskModerate

added risk

Low

added risk

LowLow

added riskadded risk1-2 risk factors

Established CV

or renal disease

Moderate

added risk

Cardiovascular event rate in 10 yearsCardiovascular event rate in 10 years

Risk for cardiovascular death in

10 years (SCORE)

Risk for cardiovascular death in

10 years (SCORE)

Lifestyle Changes

�weight reduction,

�adopting the Dietary approaches to Stop Hypertension (DASH)

eating plan,

�limiting alcohol consumption,

�smoking cessation, and, importantly,

�limiting salt intake to < 2.4 g/day

�engaging in physical activity,

Εxercise capacity and Mortality in Hypertensive Men

With and Without Cardiovascular Risk Factors

Risk Factors

No Risk Factors

* p<0.007

† p=0.016

1.0

1.5*

1.000.97

1.47

Mortality Risk

Kokkinos P, A. Pittaras, Manolis AJ et al. Hypertension 2009;53

0.0

0.5

≤5 METs

0.660.48

0.370.33

0.56

5.1-7 METs 7.1-10 METs >10 METs

*

*

**

* †

* Different from the very-low-fit (≤ 5 Mets) with no risk factors

† Different from the low-fit (5.1 to 7 METs) with risk factors

Mortality Risk

Exercise Capacity and Mortality in Diabetics

Kokkinos P, Manolis AJ et al. Diabetes Care 2009

Which is the Blood Pressure Target?

GOALS OF ANTIHYPERTENSIVE

TREATMENT

BP reduction

2007 ESH/ESC Guidelines

BP Thresholds / Targets (mmHg)

General HT population

≥ 140/90

High risk patients

(CAD/Cerebrovasc. disease/

Diabetes/Renal dysfunction)

≥ 130/85Threshold ≥ 140/90

< 140/90

≥ 130/85

< 130/80

Threshold

Target

Concept of flexible threshold/target

for treatment in relation to total CV risk

Diabetes: Tight Glucose vs Tight BP Control and CV

Outcomes in UKPDS

Stroke

Any Diabetic

Endpoint

DM

Deaths

Microvascular

Complications

-10

0

% Reduction In Relative Risk

10%12%

5%

-50

-40

-30

-20

% Reduction In Relative Risk

Tight Glucose Control(Goal <6.0 mmol/l or 108 mg/dL)

Tight BP Control(Average 144/82 mmHg)

32%

37%

32%

24%

44%

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

*

*

*

**P <0.05 compared to tight glucose control

20

25

HOT Diabetic Subgroup

Reduction in Cardiovascular Events

Number of events*

per 1000 patient-yrs

P=0.005

Target

diastolic BP

(mmHg)

Achieved†

systolic

BP

(mmHg)

Achieved†

diastolic

BP

(mmHg)

# of patients with

diabetes

≤≤≤≤ 90 143.7 85.2 501

0

5

10

15

Hansson L, et al. Lancet. 1998;351:1755–1762.

Number of events*

per 1000 patient

*Includes all myocardial infarction, all strokes, and all

other cardiovascular deaths

≤≤≤≤ 90 143.7 85.2 501

≤≤≤≤ 85 141.4 83.2 501

≤≤≤≤ 80 139.7 81.1 499†mean of all blood pressures for all study patients in BP subgroups from 6 months of follow-up to end of study

AIM: A multicenter, randomized, comparative trial to test if

the intensive control of

� glycaemia,

ACCORD

� blood pressure,

� lipids,

can reduce the risk of major cardiovascular events in high

risk type 2 diabetic patients.

140

130

(mmHg)Standard

Mean 133.5 mmHg

1.0

0.8

0.60.0

0.1

0.2 Standard

Intensive

Proportion with events

BP and CV Events in ACCORD

SBP Primary outcome

The ACCORD Study Group, NEJM 2010; March 14

120

110

0

0 1 2 3 4 5 6 7 8

Years since randomization

Intensive

Mean 119.3 mmHg

Mean no. of

medications

prescribed

Intensive

Standard

No. of patients

Intensive

Standard

3.2

1.9

2174

2208

3.4

2.1

2071

2136

3.4

2.1

1973

2077

3.5

2.2

1792

1860

3.5

2.2

1150

1241

3.5

2.3

445

504

3.4

2.3

156

203

3.4

2.3

156

201

0.4

0.2

0.00 1 2 3 4 5 6 7 8

0 1 2 3 4 5 6 7 8

0.0

Years

P = 0.20

DBP: 70 vs 62 mm Hg

Nonfatal MI

HR RR

0.87

P

0.25

Relative Risk of Stroke / MI in ACCORD

Stroke

0.5 1.0 2.0

Favours standard therapyFavours intensive therapy

0.59 0.01

Intensive: SBP 119.3 mmHg

Standard: SBP 133.5 mmHg

The ACCORD Study Group, NEJM 2010

Safety and Efficacy of Low BP Among Patients with DiabetesSafety and Efficacy of Low BP Among Patients with Diabetes

Subgroup Analysis from the ONTARGET Subgroup Analysis from the ONTARGET

Redon J et al. J Am Coll Cardiol 2012;59:74

150

150

149150

160

162

154155

160

170

Diabetes PreviousPrevious CVDCVD

SBP (SBP (mmHg)) SBP (SBP (mmHg))

PLPL

Stroke CHD

Achieved BP in TrialsAchieved BP in Trials

132

129130

124

136

130130

122

140

136

130

124

133

128

138

135

140

136

141

132

143

100

110

120

130

140

136

133133

119

144

141

145

143144

140

137

128

138

132

140

134

143

134

153

143

139

154

144

155

145

148

145

110

120

130

140

150

BP BP ∆∆∆∆ ∆∆∆∆ BenefitBenefit No benefit No benefit

Zanchetti, Grassi, Mancia J Hypert 2009; 27: 923

HOTHOTSHEPSHEP

UKPDSUKPDS S. S. EurEur ADVADV ABCDABCDRENRENHOPEHOPE PROGPROG

HTHT

IDNTIDNT

AMAMNTNT IRIR

IDNTIDNT

PLPL

ActiveActive

PATSPATS

ActiveActive

PROGPROG

ACCACC

PROFPROF

HOPEHOPE

EUEU

CAMCAM--AMAM PREVPREV

ACTACT

CAMCAM--ENEN

PEAPEATRTRACRDACRD

NAVNAV

preDMpreDM

Diabetes Mellitus - Drug Treatment Recommendations

� Initiation at SBP ≥ 140 mmHg

� Target BP < 140/85 mmHg

2013 ESH/ESC Hypertension Guidelines2013 ESH/ESC Hypertension Guidelines

� All drug classes are useful

� Combination treatment most often to be considered

Choice Of Antihypertensive Drugs -

Conclusions From 2013 (And 2003 And 2007) Guidelines

2013 ESH/ESC Hypertension Guidelines

� The main benefits of antihypertensive treatment are due to lowering BP

“per se” and are largely independent of the drug employed

� Although meta-analyses occasionally claim superiority of one class for

some outcomes this largely depends on selection bias of trials. The

largest meta-analyses do not show clinically relevant between-class

differences

� Current Guidelines reconfirm that the following drugs classes are all

suitable for initiation and maintenance of antihypertensive treatment

either as monotherapy or in some combinations with each other (IA)

�Diuretics (thiazides / chlorthalidone / indapamide)

�Beta-blockers

�Calcium antagonists

�ACE-inhibitors

�Angiotensin receptor blockers

Target BP

(mm Hg)

Average Number of Antihypertensive Agents

1

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

Trial 2 3 4

Multiple Antihypertensive Agents

are Needed to Achieve Target BP

AASK MAP <92

MDRD MAP <92

HOT DBP <80

IDNT SBP/DBP 135/85

UKPDS = United Kingdom Prospective Diabetes Study;

ABCD = Appropriate Blood Pressure Control in Diabetes;

MDRD = Modification of Diet in Renal Disease; HOT = Hypertension Optimal Treatment;

AASK = African American Intervention Study of Kidney Disease;

IDNT = Irbesartan Diabetic Nephropathy Trial.Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

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

ACCOMPLISH

SBP over time Kaplan-Meier for primary endpoint

mmHg

ACEI / HCTZN=5733

CCB / ACEI

Cumulative event rate

20% Risk ReductionACEI / HCTZ

CCB / ACEI650

Month

5731 5387 5206 4999 4804 4285 2520 1045

5709 5377 5154 4980 4831 4286 2594 1075Pts.

*Mean values are taken at 30 months F/U visit

129.3 mmHg

130 mmHg

Difference of 0.7 mmHg p<0.05*

DBP: 71.1 DBP: 72.8

CCB / ACEIN=5713

HR (95% CI): 0.80 (0.72, 0.90)

Time to 1st CV morbidity/mortality (days)

p = 0.0002

526

ACCOMPLISH ACCOMPLISH TrialTrial

� 50% of patients were obese

� 60% of patients had Diabetes Mellitus

� 97% of patients were treated previously for

hypertensionhypertension

� 74% of patients were treated with ≥ 2

antihypertensive agents

� Only 37.5% of patients were controlled to <140/90

mmHg

2013 ESH/ESC Guidelines

Combinations Between Some Classes

of Antihypertensive Drugs

Thiazide diureticsThiazide diuretics

ßß--blockersblockers ATAT11--receptorreceptor

antagonistsantagonists

Thiazide diureticsThiazide diuretics

ATAT11--receptorreceptor

antagonistsantagonists

ACCOMPLISHACCOMPLISH

ADVANCEADVANCE

HYVETHYVET

ASCOTASCOT

ONTARGETONTARGET

ACE inhibitorsACE inhibitors

Calcium Calcium

antagonistsantagonists

αα--blockersblockers

ACE inhibitorsACE inhibitors

Calcium Calcium

antagonistsantagonists

•• Pronounced antihypertensive effectPronounced antihypertensive effect

•• CV protectionCV protection

•• Optimal tolerabilityOptimal tolerability

ACCOMPLISH: ACE-I

ADVANCE: ACE-I

HYVET: ACE-I

ASCOT: ACE-I

ON TARGET: ACE-I

Selecting Patients Suitbale for RAS Blockade with

CCB or Diuretic

RAS blocker

CCB Thiazide diuretic

� Metabolic syndrome

� Impaired fasting glucose

� Family history of diabetes

� Lipid profile alterations

� Need to avoid hypokalemia

� No metabolic problems

� Low risk of developing

diabetes

� Hypervolemia

� Advanced nephropathy

GOALS OF ANTIHYPERTENSIVE

TREATMENT

BP reduction

Risk

Factors

HT

Prevention

NOD

PreventionESRDAF

PreventionCHD StrokeCHF Cognitive

Dysfunction

TOD

regression/

prevention

Dysfunction

Dementia

� LVH

� IMT

� Microalbuminaria

� Arterial stiffness

� Endotheliadysfunction

� Cardiacfibrosis

The CV continuum in HTN and the relative prevention of BP

lowering and the ancillary action of drugs.

Zanchetti A. J Hypertens 2005;23:113

Drugs To Be Preferred In Specific Conditions

2013 ESH/ESC Hypertension Guidelines2013 ESH/ESC Hypertension Guidelines

Results of a Meta-analysis for Incident Diabetes -

Twenty-two Clinical Trials of 143,153 Hypertensive Patients

ARB

ACE inhibitor

CCB

0.57 (0.46-0.72) p < 0.0001

0.67 (0.56-0.80) p < 0.0001

0.75 (0.62-0.90) p = 0.002

Elliott WJ, Lancet 2007; 369: 201

Placebo

Beta-blocker

Diuretic

0.77 (0.63-0.94) p = 0.009

0.90 (0.75-1.09) p = 0.30

Referent

50 70 90 126

Odds ratio of incident diabetes Incoherence = 0.000017

2525

3030

20/9320/93

20/8320/83

PP=0.007=0.007

PP=0.048=0.048

25/9425/94

PP=0.002=0.002

Development of new-onset diabetes*

ATAT11 blocker + HCTZ blocker + HCTZ

Calcium Antagonist + ACE inhibitorCalcium Antagonist + ACE inhibitor

Percentage of Patients

Percentage of Patients

Losartan/HCTZ increased the incidence of new onset type 2 Diabetes Mellitus more significantly than verapamil SR/trandolapril following OGTT by study end*

* Fasting blood glucose ≥126mg/dl and/or

2-hour blood glucose levels after OGTT

≥200mg/dl based on ADA definition

00

55

1010

1515

2020

2525

Week 12Week 12 Week 52Week 52

6/866/86

20/9320/93

10/7210/72

End ofEnd ofstudystudy

10/9110/91

Percentage of Patients

Percentage of Patients

Bakris G et al: Diabetes Care. 2006;29(12):2592-7

Arterial Compliance Changes in Diabetic

Normotensive Patients after ACE-I therapy

12

14

PWV(m/sec)

*

**

PWV at beseline and Post treatment

with Perindopril in Normotensives with DM

0

2

4

6

8

10

Type II DM

*P<0.003, **P<0.001

Baseline

Post treatment

PWV(m/sec)

Manolis AJ et al. Am.J. HypertensH 2005;18:18

All Type I DM

Ideal Antihypertensive in the Patient With

Diabetes

� Does not worsen Insulin resistance

� Does not cause - Hyperglycemia

- New-onset diabetes

- Dyslipidemia

� Protects kidney and heart

Take Home Messages

� Hypertension occurs in 75% of patients with type 2

diabetes

� Hypertension in patients with type 1 diabetes is also

common

� Hypertension is a promoter of macro- and � Hypertension is a promoter of macro- and

microvascular disease

� There is evidence to link the RAAS with hypertension

in patients with obesity, metabolic syndrome, and

patients with type 2 diabetes

www.hypertension2014.orgwww.hypertension2014.orgwww.hypertension2014.orgwww.hypertension2014.org

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