Download - HTA Si Sindromul Metabolic
![Page 1: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/1.jpg)
HTA si sindromul metabolic
Prof. Doina Dimulescu, MD, PhD, FESC
Clinica de Cardiologie Elias Bucuresti
![Page 2: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/2.jpg)
Obesity in USA during 1995-2005
![Page 3: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/3.jpg)
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)
![Page 4: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/4.jpg)
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)
![Page 5: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/5.jpg)
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)
![Page 6: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/6.jpg)
Components of cardiovascular dysmetabolic syndrome
Braunwald 2008
![Page 7: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/7.jpg)
Inflamation and obesity
![Page 8: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/8.jpg)
• Plasma renin and epinephrine activity variation during treadmill test in lean vs obese patients
Antman 2007
![Page 9: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/9.jpg)
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
![Page 10: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/10.jpg)
Global projections for the diabetes epidemic:1995-2010
![Page 11: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/11.jpg)
PAPERS PUBLISHED IN ATVB ON DIABETES
0
40
80
120
160
200
YEAR
NU
MB
ER O
F PA
PER
S
Cohen ATVB 2004; 24: 1340 – 1341.
GET TO KNOW THE ENEMY
![Page 12: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/12.jpg)
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
![Page 13: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/13.jpg)
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
![Page 14: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/14.jpg)
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
![Page 15: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/15.jpg)
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
![Page 16: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/16.jpg)
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
![Page 17: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/17.jpg)
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
![Page 18: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/18.jpg)
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
![Page 19: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/19.jpg)
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
![Page 20: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/20.jpg)
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
![Page 21: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/21.jpg)
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
![Page 22: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/22.jpg)
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
![Page 23: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/23.jpg)
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
![Page 24: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/24.jpg)
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
![Page 25: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/25.jpg)
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
![Page 26: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/26.jpg)
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
![Page 27: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/27.jpg)
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
![Page 28: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/28.jpg)
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
![Page 29: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/29.jpg)
2007 Guidelines for the Management of Arterial Hypertension
Journal of Hypertension 2007;25:1105-1187
European Society of Hypertension European Society of Cardiology
![Page 30: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/30.jpg)
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
![Page 31: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/31.jpg)
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)
![Page 32: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/32.jpg)
Choice of Antihypertensive Drugs
• The main benefits of antihypertensive therapy are due to lowering of BP per se
![Page 33: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/33.jpg)
Bood Pressure Lowering Treatment Trialists Collaboration
The Lancet 2003
![Page 34: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/34.jpg)
Trials comparing the effect on primary endpoint of tratments based on different
antihypertensive drugs
Braunwald 2008
![Page 35: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/35.jpg)
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
![Page 36: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/36.jpg)
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
![Page 37: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/37.jpg)
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
![Page 38: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/38.jpg)
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
![Page 39: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/39.jpg)
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
![Page 40: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/40.jpg)
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
![Page 41: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/41.jpg)
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
![Page 42: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/42.jpg)
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
![Page 43: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/43.jpg)
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
![Page 44: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/44.jpg)
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
%
![Page 45: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/45.jpg)
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)
![Page 46: HTA Si Sindromul Metabolic](https://reader033.vdocuments.pub/reader033/viewer/2022061610/577cc77b1a28aba711a110ef/html5/thumbnails/46.jpg)
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