HTA si sindromul metabolic

Prof. Doina Dimulescu, MD, PhD, FESC

Clinica de Cardiologie Elias Bucuresti

Obesity in USA during 1995-2005

Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326; doi:10.1093/eurheartj/ehm604

Mortalitatea prin boala cerebrovasculara in diferite regiuni ale Europei

(barbati,femei 45-74 ani)

Copyright restrictions may apply. Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326;

Mortality by Ischemic Heart Disease in Different Regions of Europe

(Males, Females, 45-74y)

Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326; doi:10.1093/eurheartj/ehm604

Mortality by Ischemic and Cerebrovascular Disease in Different Regions of Europe

(Males, Females, 45-74 y)

Components of cardiovascular dysmetabolic syndrome

Braunwald 2008

Inflamation and obesity

• Plasma renin and epinephrine activity variation during treadmill test in lean vs obese patients

Antman 2007

Metabolic syndrome and diabetes mellitus

• Metabolic syndrome – min. two of the following conditions:

- abdominal obesity- insulin resistance (FG)- hypertension- dyslipidemia (TG, HDL-C)- microalbuminuria

• Co-existance of MS and DM – prevalence of coronary disease reaches 19,2% of population (in the absence of MS the prevalence of CD in pts with DM is low -7,5%, similar to the population without DM (8,7%)

Alexander CM et al, Diabetes 2003; 52:1210-4

Global projections for the diabetes epidemic:1995-2010

PAPERS PUBLISHED IN ATVB ON DIABETES

0

40

80

120

160

200

YEAR

NU

MB

ER O

F PA

PER

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Cohen ATVB 2004; 24: 1340 – 1341.

GET TO KNOW THE ENEMY

CV RISK FACTORS CLUSTER TOGETHER

THE DIABETIC POPULATIONTHE DIABETIC POPULATION

2%

3%

1%

3%1%

0%

1%

DYSLIPIDEMIADYSLIPIDEMIA

9 % of US 9 % of US popln has popln has

diabetes and diabetes and dyslipidemiadyslipidemia

OBESITYOBESITY

7 % of US 7 % of US popln has popln has

diabetes and diabetes and obesityobesity

HYPERTENSIONHYPERTENSION

6% of US popln 6% of US popln has diabetes and has diabetes and

HBPHBP

11% of the US 11% of the US adult population adult population has diabetes, but has diabetes, but only 0.1% has no only 0.1% has no co-morbidity.co-morbidity.NHANE Survey, 1988 - 94

ObesityAssociation with hypertension

• Wight gain +5 kg over the age of 18 y –increases with 60% the risk ofdevelopping hypertension

• +10Kg – increases 2,2 fold the risk of hypertension

• Framingham Study: 70% of hypertension in men and61% in women –attribuable to excess adiposity

• Obesity- accompanied by hypertension-related outcomes: stroke, heart failure

Kaplan 2006

Mechanisms of hypertension in METS

• Volume-expansion due to obesity• Increased cardiac output• Failure of systemic vascular resistances to

decrease for balancing the high output• Hyperinsulinemia ( endothelial

dysfunction, endogenous AT II production, activation of sympathetic nervous system)

• Impaired normal vasodilatatory effect of insulin by impaired NO synthesis

Kaplan 2006

Mechanisms of hypertension in METS (II)

• Insulinresistance• Increased RAAS activity• Increased leptin• Increased ET-1• More intense inflamation• Increased renal sodium retention Most of these reflect insulin-resistance and

hyperinsulinemiaKapalan 2006

Leptin resistance and cardiovascular risk

• Leptin –regulatory key of energy balance• Increased circulating Leptin –marker of Leptin

resistance –common in obesity• Leptin has structural and functional resemblance

to proinflamatory cytokines (IL-6) and may modulate CRP

• Leptin regulates components of innate and adaptive immunity (T lymfocites and monocytes)

• Convergence of increased levels of leptin and inflamation markers in CVD

JACC, Oct 2008

Leptin resiatance Pathways to cardiovascular risk (I)

• Immunity, inflamation, atherosclerosis (direct atherogenic effect, leptin receptors in plaques; activation of T cells, pro-inflamatory immune response)

• The relation of leptin ans subclinical atherosclerosis in obese humans requires further study

• Positive CV prediction (acute events –sroke, MI) for both inflamatory markers and leptin

Leptin resiatance Pathways to cardiovascular risk (II)• Insulin resistance and diabetes –leptin as

an insulin- sensitising hormone ?• Basal plasma leptin and insulin parallel

each other• Insulin and glucose appear to stimulate

leptin secretion in adipocytes• Increased leptin is associated with

hyperinsulinemia and insulin-resistance, independent of BMI

JACC 2008

Leptin resiatance Pathways to cardiovascular risk (III)• In response leptin decreases insulin

secretion by direct effect on pancreatic β-cells, might reduce lipotoxicity of TG and improve whole body insulin sensitivity

• Leptin therapy-dissapointing in obesity trials (leptin resistance?), but improved diabetic measures in patients with familial leptin defficiency and lipoatrophic diabetes

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210

Cellular and molecular Leptin pathophysiology

Leptin resiatance Pathways to cardiovascular risk

(IV)• Hypertension• Increasing leptin levels with increased BP

levels (especially in hypertensive, obese woman)

• Chronic leptin-mediated central (hypotalamus) sympathetic activation – pressor effects –role in obesity-mediated hypertension

Leptin resistance Pathways to cardiovascular risk (V)• Thrombosis• Leptin enhances platelet aggregation and

may promote arterial thrombosis (might be limited to obese patients)

• Leptin levels-possible correlation with PAI-1, VWFactor, Fg, F VIIa

Leptin resistance Pathways to cardiovascular risk

(VI)• Myocardial injury• Decreased myocyte contractility• Increased O2 reactive species• Reduced NO• Proinflamatory factors• Cardyomyocites hypertrophy,

prolipheration, apoptosis –maladaptive cardiac remodelling in obese patients

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210

Overview of Leptin Resistance and Hyperleptinemia in Obesity-Related Cardiovascular Disease

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210

Overview of Leptin Resistance and Hyperleptinemia in Obesity-Related Cardiovascular Disease

Does the METS predict CV risk beyond its components?

• 6 definitions of METS: WHO, NCEP updated, EGIR, ACE, IDF

• Imprecise definitions, uncertain pathogenesis, ambiguous value as CV risk factor

• A prospective population-based study , 13 y follow-up, 1025 nondiabetic subjects (65-74Y/o) that met criteria for METS;

Eur Heart J 2007

Does the METS predict CV risk beyond its components?

• METS defined by all 6 criteria predicted CVD mortality in elderly population (1,32-1,56 fold risk)

• METS cefinition by WHO, ACE, IDF predicted CHD mortality (1,42-1,58 fold risk)

• METS did not predict CVD mortality byond and above of 4 of his single components (IFG, IGT, low HDL C, HRs for CVD mortality

Eur Heart J 2007JACC 2006

Does the METS predict CV risk beyond its components?

• IGT and microalbuminuria predicted most consistently CVD and CHD mortality

• WHO and ACE criteria predicted most consistently CVD and CHD mortality

• METS defined by NCEP crit was not associated with a greater risk of early-onset coronary disease than individual components (HDL, HTA, IFG)

Eur Heart J 2007JACC 2006

2007 Guidelines for the Management of Arterial Hypertension

Journal of Hypertension 2007;25:1105-1187

European Society of Hypertension European Society of Cardiology

Goals of Treatment• In hypertensive patients, the primary goal of

treatment is to achieve maximum reduction in the long-term total risk of cardiovascular disease

• This requires treatment of the raised BP per se as well as of all associated reversible risk factors

• BP should be reduces to at least below 140/90 mmHg (systolic/diastolic) and to lower values, if tolerated, in all hypertensive patients

Goals of Treatment

• Target BP should be at least <130/80 mmHg in diabetics and in high or very high risk patients, such as those with associated clinical conditions (stroke, myocardial infarction, renal dysfunction, proteinuria)

Choice of Antihypertensive Drugs

• The main benefits of antihypertensive therapy are due to lowering of BP per se

Bood Pressure Lowering Treatment Trialists Collaboration

The Lancet 2003

Trials comparing the effect on primary endpoint of tratments based on different

antihypertensive drugs

Braunwald 2008

Antihypertensive therapy in diabetic patients

• ACEI (HOPE)• ARBs (LIFE, RENAAL)• Calcium channel blockers (HOT, Syst-Eur)• Betablockers (UKPDS)• Diuretics (ALLHAT)

ESC/EHS Guidelines 2007JNC -7 Guidelines for recommended drugs for patients with compelling indications

JAMA 2002; 288:2981-2997

ALLHAT: Serum glucose

05

101520253035

Fast

ing

gluc

ose

>12

6 m

g/dL

(%

)

Baseline 2 years 4 years

Chlorthalidone Lisinopril Amlodipine

JAMA 2002; 288:2981-2997

ALLHAT: De Novo DM

0.0

2.0

4.0

6.0

8.0

10.0

12.0

Even

ts (

%)

Chlorthalidone Lisinopril Amlodipine

Comparatia BB vs ARB in terapia antihipertensiva asupra riscului de

evenimente CV

www.cardiosource.com

LIFE

Lancet 2002; 359: 995-1003.

%

Results• BP by 30.2/16.2 in losartan arm and 29.1/16.8 in atenolol arm (p=0.017 for SBP; p=0.37 for DBP)• Primary composite endpoint in losartan arm (Figure), as was stroke and new onset diabetes but no difference in CV mortality (Figure)Conclusions• Unlike CAPPP, NORDIL and STOP-HTN2 trials which compared ACE inhibitors or calcium channel blockers with beta blockers and diuretics for treatment of hypertension, LIFE showed a significant treatment effect with use of the angiotensin II type 1-receptor antagonist losartanLimitations• High risk HTN patients selected for study; generalizability to lower risk patients cannot be made• No comparison of losartan to diuretic

Trial Design: LIFE was a multi-center randomized trial of losartan (an ARB) compared with atenololalone in prevention of coronary events in patients with hypertension (HTN) and LVH. Mean follow-upwas 4.8 yrs. Primary endpoint was a composite of death, MI and stroke.

11

13

45 5

76

8

0

5

10

15

20

Losartan Atenolol

PrimaryComposite

HR 0.87p=0.021

CVMortalityHR 0.89p=0.206

Stroke

HR 0.75p=0.001

New onsetDM

HR 0.75p=0.001

DZ nou aparut in studii clinice de terapie antihipertensiva

Trial Tr. Comp. New DM rates (%)

p Value for RR

HOPE ACEI vs CT 3.6 vs 5.4 <0.001

ALLHAT CCB vs CT 9.8 vs 11.6 <0.04

ALLHAT ACEI vs CT 8.1 vs 11.6 <0.001

INVEST CCB vs non CCB

7.0 vs 8.2 <0.005

LIFE ARB vs CT 6.0 vs 8.0 <0.001

VALUE ARB vs CCB 13.1 vs 16.4 <0.0001

Williams JACC 2005

Previously known diabetes

Verdecchia et al Hypertension 2004

Probability of event-free survival%100

90

80

70

60

50

40

30

Time to event (years)0 3 6 9 12 15

No diabetes

New-onset diabetes

A

C

B

p<0.0001

A B CGroups

0

1

2

3

4

5

0.97

3.90

4.70

Rate of eventsper 100 patient-years

Evenimente CV la pacienti hipertensivi tratati, fara DZ, cu DZ nou aparut si cu DZ vechi

Diabetul nou aparut sub terapie antihipertensiva

Efecte diabetogene ale diureticelor si betablocantelor care se translateaza in alterarea prognosticului

- cresterea glicemiei indusa de tratament la pacienti in varsta de 50 de ani a fost un predictor major pentru IM la 60 ani

Dunder K et al, BMJ 2003; 326:681-8

Choice of Antihypertensive Drugs

• β-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes

ESC/ISH Guidelines 2007

Antihypertensive Treatment in Diabetics

• A blocker of the renin-angiotensin system should be a regular component of combination treatment and the one preferred when monotherapy is sufficient

ESC/ISH Guidelines 2007

Betablocantele la diabetici sant sigure?Sant toate BB la fel?

www.cardiosource.com

-9.1

-2.0

-10

-5

0

Results• Mean change in HbA1c from baseline ↑ in metoprolol group vs carvedilol (Figure)• Study drug discontinuation due to worsening glycemic control ↑ in metoprolol group (2.2% vs 0.6%, p=0.04)• Reduction in HOMA-IR from baseline greater in carvedilol group (Figure) • Triglyceride ↑ greater in metoprolol group (13.2% vs 2.2%, p<0.001)Conclusions• Among patients with hypertension and type 2 diabetes taking a renin-angiotensin system blocker, treatment with carvedilol was associated with more stabilized glycemic control and improved insulin resistance compared with metoprolol when used to acheive target blood pressure goals• Larger trial would be needed to determine if improvements in glycemic control and insulin resistance with carvedilol would translate into differences in clinical outcomes

0.02

0.15

0.0

0.1

0.2

GEMINI

Change in HOMA-IRfrom Baseline

p = 0.004

Trial Design: GEMINI was a randomized, double-blind study of the effect of beta-blocker administration withcarvedilol (6.25 to 25 mg dose, twice daily) (n=498) or metoprolol tartrate (50 to 200 mg dose, twice daily)(n=737) on glycemic control among patients with hypertension and type 2 diabetes. Primary endpoint waschange from baseline HgA1C following 5 months of maintenance therapy.

Presented at AHA Scientific Sessions 2004

Carvedilol Metoprolol

Change in HbA1cfrom Baseline

p < 0.001

%

2

Losartan

4

68

1012

1416

Eprosartan Irbesartan Valsartan Candesartan Telmisartan

Fold activation

Olmesartan

5 micromolar

Ability of Different ARBs To Activate PPAR (S.C. Benson et al., Hypertension, 43:993-1002, 2004)

ONTARGET

• Telmisartan (16.7%) noninferior; combination (16.3%) not superior to ramipril (16.5%) for primary endpoint (CV death, MI, stroke, heart failure)

• Greater incidence of hypotension in combination (4.8%) and telmisartan (2.7%) groups, compared with ramipril group (1.7%) (p < 0.001)

Trial design: Patients at high risk for cardiovascular events, but without heart failure, were randomized to telmisartan, ramipril, or the combination. Patients were followed for a median of 56 months.

Results

Conclusions

The ONTARGET investigators. N Engl J Med 2008;358:1547-59

Telmisartan(n = 8,542)

Combination(n = 8,502)

• Either telmisartan or ramipril, but not both, can be used in hypertensive patients at high risk for cardiovascular events

• Side effects greater with combination therapy

16.7 16.3

%

0

10

Primary endpoint

20

Ramipril(n = 8,576)

16.5

0

10

15

5

Mortality

11.6 12.5 11.8

%

(p < 0.004*) (p = ns)

* Telmisartan vs. ramipril for noninferiority