A KARDIOMETABOLIKUS KOCKÁZAT Prof. Dr. Farsang Csaba Szt. Imre Kórház Kardiometabolikus Centrum
Innovatív Gyógyszerek Kutatására Irányuló Nemzeti Technológiai Platform Munkaértekezlet 2009. április.20.
2007 ESH / ESC Guidelines
Factors Influencing Prognosis: Risk factors • • • • •
• • •
Systolic and diastolic BP levels Levels of pulse pressure (in the elderly)Metabolic syndrome Age (M > 55 years; W > 65 years) Smoking Note : the cluster of 3 out of 5 risk factors among Dyslipidaemia - BP ≥ 130/85mmHg - Total Cholesterol > 5.0 mmol/l (190 mg/dl) - low HDL-cholesterol or : LDL-C > 3.0 mmol/l (115 mg/dl) - high TG or : HDL-C: M < 1.0 mmol/l - altered fasting plasma glucose or: TG > 1.7 mmol/l - abdominal obesity Fasting plasma glucose 5.6-6.9 mmol/L Abdominal obesity (Waist circumference > 102 the cm (M), > 88 of …indicates presence cm (W)) metabolic syndrome Family history of premature CV disease (M at age < 55 years; W at age < 65 years)
Teljes kardiovaszkuláris kockázat tényezői Klasszilus rizikótényezők Lpr, PP, PWV, TC, BKI, eGFR MAU, CRP?, Hcys?, ↑ LDL-C
↑ VNY
↑Dohányzás
Új kockázati tényezők
Metaboli kus sszindróma zindróma Metabolikus ↓ HDL-C
↑TNFα α ↑Insulin Abdominalis Obesitas ↑ IL-6 ↑ Glu ↑PAI-1 ↑ TG
T2DM
KARDIOVASZKULÁRIS BETEGSÉG
Teljes kardiovaszkuláris kockázat tényezői Új kockázati tényezők
Klasszilus rizikótényezők
Metaboli kus sszindróma zindróma Metabolikus
Lpr, PP, PWV, TC, BKI, eGFR MAU, CRP?, Hcys?, ↑ LDL-C
K
a
r
d
↑ VNY
i
o
m
↓ HDL-C
↑Dohányzás
e
t
a
b
↑TNFα α ↑Insulin Abdominalis Obesitas ↑ IL-6 ↑ Glu ↑PAI-1 ↑ TG
o
l
i
k u s
r
T2DM i
z i
KARDIOVASZKULÁRIS BETEGSÉG
k ó
Teljes kardiovaszkuláris kockázat tényezői Új kockázati tényezők
Klasszilus rizikótényezők
Metaboli kus sszindróma zindróma Metabolikus
Lpr, PP, PWV, TC, BKI, eGFR MAU, CRP?, Hcys?, ↑ LDL-C
↑ VNY
↓ HDL-C
↑Dohányzás
↑TNFα α ↑Insulin Abdominalis Obesitas ↑ IL-6 ↑ Glu ↑PAI-1 ↑ TG
T2DM
↑ Húgysav K
a
r
d
i
o
m
e
t
a
b
o
l
i
k u s
r
i
z i
KARDIOVASZKULÁRIS BETEGSÉG
k ó
A kardiometabolikus kockázat definiciója A metabolikus syndroma klinikai diagnózisa önmagában nem elegendő a kardiovaszkuráris betegség teljes kockázatának becslésére. A teljes kockázat meghatározásához a klinikai gyakorlatban az alábbiakat is szükséges figyelembe venni : - a tradicionális rizikófaktorokat (dohányzás; összkoleszterin szint, LDLc, CRP, húgysav, homocystein, mikroalbuminuria, BKI, PWV, PP…); - intraabdominalis obesitás; - insulin resistentia és a - kapcsolódó kockázati tényezők; Az így fugyelembe vett teljes kockázatot nevezzük globalis kardiometabolikus kockázatnak. zatnak
Kardiometabolikus kockázat: patofiziológiai kapcsolatok hasi ízás hasi elh elhízás iinzulin nzulin rrezisztencia ezisztencia
+
hhyperinsulinemia yperinsulinemia
gglucose lucose m etabolismus metabolismus ± glucose intolerancia
hhúgysav úgysav m etabolismus metabolismus húgysav vizelet húgysav clearance
ddyslipidemia yslipidemia TG PP lipemia HDLHDL-C PHLA small dense LDL ApoA1/ApoB
hemodynamika hemodynamika SNS aktivitás Na retentio hypertonia
Car -Ren-Cer-Vasc betegs ég Car-Ren-Cer-Vasc betegség
újabb újabbrizikó rizikó faktorok faktorok CRP PAI-1 Fibrinogen OSAS…
WORLD Attributable Mortality by Selected Leading Risk Factors
High Blood Pressure
High BMI
›
Number Number of of Deaths Deaths (in (in thousands) thousands) IBLF dialogue with WHO.London.28.October.2002
Oki összefüggés a 10 leggyakoribb kockázati tényező és betegség között Elvesztett életévek
HYPERTONIA
Estimated total number of adults with hypertension Measure
n (95% CI)
Total number worldwide in 2000
972 million (957-987)
Total number worldwide in 2025
1.56 billion (1.54-1.58)
Kearney PM et al. Lancet 2005; 365:217-223.
Ischemic Heart Disease (IHD) Mortality Rate IHD mortality rate in each decade of age versus usual blood pressure pressure at the start of that decade
Lancet.360::1903.2002
Stroke Mortality Rate Stroke mortality rate in each decade of age versus usual blood pressure pressure at the start of that decade
Lancet.360: 1903.2002
Heart Failure Incidence as a Function of Hypertension Stages 10
Annual Rate/1000* Men Men Woman Woman
8
6
4
2
0 Normal <120/80 <120/80
Pre-Hypertension 120-139/80-89 120-139/80120 139/80-89
Stage 1 140-159/90-99 140-159/90140 159/90-99
Stage 2 160+/100+ 160+/100+
*Age*Age-adjusted Framingham Heart Study 1995
Participating countries Belgium Germany Hungary Italy Netherlands Norway Portugal Slovenia Spain Sweden Turkey UK
Kjeldsen SE, SE, Farsang C, NadichNadich-Brule L, Perlini S, Zidek W. J Hypertens 2008
Result: BP control rate in GOOD survey
BP control rate: 947/3370 = 28.8%
Intensive treatment of hypertension is recommanded by the European Society of Hypertension and the European Society of Cardiology (ESH/ESC) to lower BP to the following goals: At least below 140/90 mm Hg, in non-diabetic patients At least below 130/80 mm Hg, in diabetic patients
Kjeldsen SE, SE, Farsang C, NadichNadich-Brule L, Perlini S, Zidek W. J Hypertens 2008
Participating Participating Countries Countries
Latvia Belarus
Czech Republic Slovakia
Ukraina
Romania
Bosnia
Serbia
Albania
BP-CARE Study 2008
Concomitant Concomitant risk risk factors factors 100
80 59.3 ± 1.4
60
50.7 ± 2.1
(%)
40.4 ± 5.4 39.5 ± 2.9
40 23.7 ± 2.5
20
15.1 ± 1.1
11.5 ± 1.1 2.5 ± 0.4
0
TC >200 mg/dl
CHD
Metabolic Syndrome
Obesity
Diabetes
Smoking
Stroke
Renal Failure
(Cl. Creat. Creat. <60 ml/min) TC = Total Cholesterol; CHD = Coronary Heart Disease.
BP-CARE Study 2008
Patients Patients (%) (%) under under Monotherapy Monotherapy and and Combination Combination Treatment Treatment 4.8%
Albania
15.3%
Bosnia 95.2%
Belarus 84.7%
17.1%
Czech Republic
82.9%
11.0%
Average Average value value 13± 1.5%
Romania 92.2%
15.7%
89.0%
13.6%
Slovakia 84.3%
80.4%
7.8%
Latvia
Serbia
19.6%
12.4%
Ukraina 86.4%
87± ±1.5%
87.6%
Monotherapy Combination
BP-CARE Study 2008
Treated Treated Patients Patients (%) (%) with with BP BP Control Control
27.1± 3.6% 72.9± ±3.6%
< 140/90 mmHg ≥ 140/90 mmHg
BP-CARE Study 2008
Comparison of patient population according to presence/absence of metabolic syndrome (ATP III definition) and/or diabetes % 100 90 80 70 60 50 40 30 20 10 0
95.3
p<0.001
77.7
72.4 46.5
53.5 27.6
22.3 4.7
No metabolic syndrome nor diabetes
Metabolic syndrome
Diabetes
Metabolic syndrome and diabetes
BP controlled n=947 BP uncontrolled n=2,423 Kjeldsen SE, SE, Farsang C, NadichNadich-Brule L, Perlini S, Zidek W. J Hypertens 2008
A 130/80 Hgmm célvérnyomás értéket elérők aránya – diabeteses betegek (2005) %
2005
25
20
15 12,3
10
8,3
7,9 5,7
5
10,8
10,2
9,9
4,1
7.7
8,2
7,7 6,5
6
6,3
6,3
4,8
4,2 2,7
2,7
5,1
4,7
2,3
0 nya orsod dap est B Bara Bu
Bács Békéssongrá d C
r Fejé
r G yő Hajdú Heves
Jásozmá rom Nógr ád K
t gy lc s Tolna PesS omo Sz abo
Vas prém Ves z
Hypertension Register of Hung. Soc. Hypertens.
Z ala
% ág O rsz
A 130/80 Hgmm célvérnyomás értéket elérők aránya – diabeteses betegek (2007) % 2007
25 22,1
20
15
13,5
13,9
13,5 11,8
11,8
8.5
9,5
10
8,5
8,5
8,3
7,8
6,2
5,4
4,8
5,1
5
3,6 2,9
3,2
2,4
0 nya orsod dapest B Bara Bu
d s Bác Békéssongrá C
r Fejé
r ú G yő Hajd Heves
Jásozmá rom Nógr ád K
* Nógrád és Heves megyékből 2007-ben nem érkezett adat.
s t a y PesSomog z abolc Toln S
Vas zprém Ves
Zala
%
ág O rsz
Hypertension Register of Hung. Soc. Hypertens.
Blood pressure and risk factors n=534, Correlations are adjusted for sex
Cholesterol **
* * *
Triglycerides
**
**
** **
** **
BP
***
Hematocrit
*
***
Overweight
**
* Heart Rate Tecumseh BP Study, 1990.
Diabetes ***p<0.001 **p<0.01 *p<0.05
OBESITAS
Kapcsolat a rizikófaktorok között 6.6 6.6
60 60
Total cholesterol
5.8 5.8
SBP
50 50 40 40
mmol/l
2.8 2.6
30 30
2.4
Triglycerides
2.2 2.0
20 20
SBP high SBP % with high
6.2 6.2
1.8 1.6
10 10
1.4
HDL cholesterol
1.2 1.0
18 18
20 20
22 22
24 24
26 26
28 28
30 30
Body Mass Mass Index Index (kg/m²) (kg/m²) Body
32 32
0 0 34 34 Data from British Regional Heart Survey
Obesity and Coronary Heart Disease Mortality
Relative Risk Risk of of Coronary Coronary Relative Heart Disease Disease Mortality Mortality Heart
Nurses’ Nurses’ Health Health Study: Study: Women Women Who Who Never Never Smoked Smoked 66 55 44 33 22 11 00
<<1199
1..99 22--2244..99 55--2266..99 77--2288..99 99--3311..99 1199--221 22 22 22 22 BMI BMI (kg/m (kg/m22))
≥≥3322
pp << 0.001 0.001 for for trend trend N Engl J Med ;333:677.1995
PROGNÓZIS Hypertoniás lesz 15 évesen T2 DM –t kap 23 évesen Mikroalbuminuriás lesz 32 évesen Első MI:38 éves korában Szívelégtelenség: 41 éves korában Második MI 48 évesen (túléli?)
Medical Complications of Obesity Idiopathic intracranial hypertension
Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome
Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gout
Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis
Az obesitas gyógyszeres kezelésének történetéből Az efedrin felfedezése 1924 Amfetamin származékok: Étvágycsökkentés, de t.k. idegrendszeri mellékhatások, 20 %-os hozzászokás Forgalomból kivont szerek: Preludin, Gracidin, Desopimon, Adipex, Isolipan, Acomplia…
Orlistat 1999 óta Zsírfelszívódás gátlása (30 % kiürül) 8-10 % testsúlycsökkenés diétával együtt/év XENDOZ vizsgálat: DM incidencia Ch Ha a diéta nem zsírszegény súlyos Gi mellékhatások (olajos széklet, urgencia, flatus with discharge) 12 000 doboz/év
Sibutramin Serotonin-noradreanalin reuptake inhibitor (SNRI) Telítettségérzést fokozza, thermogenesist növeli Több mint 10 000 betegen vizsgálták: Ch , HDL-Ch + 21 %, Tg -16 % adiponectin , visc.zsír 22 % , leptin , HbA1c 50 000 doboz/év Vizsgálatok, STORM és SCOUT
ADAGIO
HDL-C percent change at 1 year
ITT population
(Mean percent change +/- SEM) from baseline Placebo Rimonabant 20 mg
13 Percent change in HDL-C (%)
11 9
8.7%
7
7.37% vs Pbo
5
p<0.0001
3
1.8%
1 -1
Days in the study
-3
n
D-7
D14
D120
D180
D270
D364
LOCF
377
371
312
285
249
217
377
388
381
330
307
281
250
388
Change from baseline in small LDL particles (%) ITT, LOCF*
(Mean change +/- SEM) from baseline Weeks
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
LOCF
0
Change in relative proportion of small LDL particles
-1
Placebo Rimonabant 20 mg
-2
-2.44 ± 0.86
-3 -4 -5 -6 -7 -8
-7.78 ± 0.88
-9 -10
* LOCF excluding data after any change in lipid modifying agents
-6.46 ± 1.10 vs Pbo p<0.0001
ADAGIO
TG percent change at 1 year
ITT population
(Mean percent change +/- SEM) from baseline
Percent change in Triglycerides (%)
Placebo Rimonabant 20 mg
n
0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 -22 -24 D-7
D14
D120
D180
D270
D364
LOCF
376
368
311
283
248
216
376
383
376
325
302
277
244
383
- 2.7%
- 17.9% vs Pbo p<0.0001
- 19.5% Days in the study
Changes in Visceral Fat Area & Subcutaneous Fat Area at 12 months
ITT, LOCF*
Subcutaneous adipose tissue
Visceral adipose tissue Mean % change from baseline (SD) Placebo n=87
Rimonabant 20 mg n=92
Mean % change from baseline (SD) Placebo n=72
Rimonabant 20 mg n=68
- 4.7
- 5.9
(10.0)
(18.9)
- 9.7 (10.4)
- 16 (17.8)
-10.08* (2.76)
p=0.0003
*LS mean difference vs pbo. on percent change - Estimate (SE)
-5.07* (1.75)
p=0.0043
Mean change and mean difference from baseline in ADIPONECTIN at 12 months ITT, LOCF Mean % change from baseline 18.89 (2.65)
23.0
5.1
Placebo n=378
Rimonabant 20 mg n=382
p<0.0001
Serious Adverse Events
Number (%) of patients with serious TEAEs, presented by primary SOC and preferred term - Randomized and exposed patients
System Organ Class preferred term
Placebo n=395
Rimonabant 20 mg n=404
PSYCHIATRIC DISORDERS Any event
2
( 0.5)
3
( 0.7)
Suicidal ideation
1
( 0.3)
2
( 0.5)
Suicide attempt
1
( 0.3)
1
( 0.2)
Acute psychosis
0
(
0)
1
( 0.2)
Anxiety
0
(
0)
1
( 0.2)
Any event
1
( 0.3)
2
( 0.5)
Dizziness
0
(
0)
2
( 0.5)
Presyncope
0
(
0)
1
( 0.2)
Cerebral infarction
1
( 0.3)
0
(
NERVOUS SYSTEM DISORDERS
0)
Blood pressure and risk factors n=534, Correlations are adjusted for sex
Cholesterol **
* * *
**
**
**
BP
**
** ** *
***
Overweight
Diabetes **
* Heart Rate Tecumseh BP Study, 1990.
Triglycerides
***
Hematocrit
***p<0.001 **p<0.01 *p<0.05
DIABETES
Incidence Incidence of of diabetes diabetes
New New cases cases of of diabetes diabetes UK UK
–
every every 10 min min
Europe Europe
––
every every 40 40 sec
USA
––
every every 20 sec sec
Campbell, Campbell, EASD-HID, EASD-HID, 2001 2001
Age-adjusted
death rate for men
Rate / 10 000 person-years
with and without diabetes at initial screening for MRFIT DM
180 160
Non-DM
160.13
140 120 100 80 60 40 20 0
65.91
53.20 17.05
CHD
6.72 1.75
Stroke
12.49
4,08
Other CVD
All deaths
Diabetes Care 1993; 16:434-444
Age-adjusted
CVD death rates by presence
of number of RF for men screened for MRFIT, with and without diabetes at baseline
CVD Death Rate per 104 140
non diab
diab
120 100 80 60 40 20 0
none
one only
two only
all three RF
Diabetes Care 1993; 16:434-444
FONTOS KÉRDÉS: Mindegyik antidiabeticum egyformán csökkenti-e a szív-érrendszeri kockázatot?
UKPDS: Original and late-follow-up relative risk reduction with metformin End point
1997: Relative risk
1997: p
2007: Relative risk
2007: p
Any diabetesrelated end point Microvascular disease
32
0.0023
21
0.013
29
0.19
16
0.31
MI
39
0.010
33
0.005
All-cause mortality
36
0.011
27
0.002
reduction (%)
Holman RR et al. N Engl J Med 2008;available at: http://www.nejm.org.
reduction (%)
Metformin on CV risk
Macrovasc. complications.
CV mortality and micro-+macrovascular complications (NS)
Survival functions for the primary (lower pair of curves) and the secondary, macrovascular (upper pair of curves) end points. Metformin treatment was not associated with an improvement in the primary end point. It was, however, associated with a decreased risk of the secondary, macrovascular end point (hazard ratio, 0.61 [95% confidence interval, 0.40-0.94; P=.02]). The number needed to treat to prevent 1 macrovascular end point was 16 (95% confidence interval, 9-67). Kooy A. et al. Arch Intern Med. 2009;169(6):616-625
Rosiglitazon biztonság End point
Rosiglitazone (n=6421) (%)
Control (n=7870) (%)
Relative risk (95% CI)
p
MI
1.46
1.05
0.02
HF
1.59
0.79
Cardiovascular mortality
0.92
0.91
1.42 (1.06–1.91) 2.09 (1.52–2.88) 0.90 (0.63–1.26)
Singh S et al. JAMA 2007; 298:1189-1195.
<0.001 0.53
Pioglitazone biztonság End point
Pioglitazone (n=8554) (%)
Hazard ratio
p
4.4
Control (n=7836) (%) 5.7
Death, MI, stroke
0.82 (0.72–0.94)
0.005
Death
2.4
2.9
0.92 (0.76–1.11)
0.38
MI
1.5
2.0
0.81 (0.64–1.02)
0.08
Stroke
1.2
1.7
0.80 (0.62–1.04)
0.09
Serious HF
2.3
1.8
1.41 (1.14–1.76)
0.002
Lincoff AM et al. JAMA 2007; 298:1180-1188.
In December 2008, the FDA issued a guidance document that recommends that all new drugs developed for the treatment of type 2 diabetes show that they do not increase the risk of cardiovascular events.
Cardiovascular safety profile of vildagliptin, a new DPP-4 inhibitor for the treatment of type 2 diabetes
Kothny V, et al. (Poster 915), EASD, Rome 2008
On April 1, 2009, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 10 to 2 that the investigational diabetes drug saxagliptin does not put type 2 diabetes patients at an increased risk for cardiovascular events.
Dow Jones Newswires, April 1, 2009. Available at http://www.wsj.com.
Blood pressure and risk factors n=534, Correlations are adjusted for sex
Cholesterol **
* * *
**
**
**
BP
** *
***
Diabetes **
* Heart Rate Tecumseh BP Study, 1990.
**
**
Overweight
Triglycerides ***
Hematocrit
***p<0.001 **p<0.01 *p<0.05
DYSLIPIDAEMIA
Relative risk of hypertension by quintiles of different lipid fractions (mg/dL) Quintile Lipid parameters/models 1st
2nd
3rd
4th
5th p for trend
TC
≤180
>180–200
>200–218
>218–243
>243
1.00
1.01
1.07
1.26
1.23
≤31
>31–38
>38–44
>44–53
>53
1.00
0.84
0.80
0.72
0.68
≤135
>135–156
>156–176
>176– 201
>201
Multivariateadjusted RR
1.00
1.08
1.10
1.37
1.39
TC/HDL-C ratio
≤3.76
>3.76–4.57
>4.57–5.49
>5.49–6.79
>6.79
Multivariateadjusted RR
1.00
0.95
1.42
1.21
1.54
Multivariateadjusted RR* HDL-C Multivariateadjusted RR Non-HDL-C
0.0067
0.0002
0.0001
<0.0001
*Adjusted for age, body-mass index, exercise, smoking status, alcohol intake, parental history of MI <60 years, and history of diabetes.
Halperin RO et al. Hypertension 2006; 47:45-50.
ILLUMINATE
Major results
Atorvastatin (n=7534), n
Atorvastatin + torcetrapib (n=7533), n
Hazard ratio (95% CI)
Major CV events
373
464
1.25 (1.09–1.44)
0.001
Deaths
59
93
1.58 (1.14–2.19)
0.006
End point
Barter PJ, et al. N Engl J Med 2007;357:2109-2122
p
KÖSZÖNÖM FIGYELMÜKET
