A KARDIOMETABOLIKUS KOCKÁZAT

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) Age (M > 55 years; W > 65 years) Smoking Abdominal obesity (Waist circumference indicates > 102 the cm (M), presence > 88 of cm (W)) metabolic syndrome Family history of premature CV disease (M at age < 55 years; W at age < 65 years) Metabolic syndrome 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 or: TG > 1.7 mmol/l glucose - abdominal obesity Fasting plasma glucose 5.6-6.9 mmol/l

Teljes kardiovaszkuláris ris kockázat tényezt nyezői Klasszilus rizikótényezők Lpr, PP, PWV, TC, BKI, egfr MAU, CRP?, Hcys?, LDL-C VNY Dohányzás Új kockázati tényezők Metabolikus szindróma HDL-C TNFα Insulin Abdominalis is Obesitas Glu PAI-1 TG IL-6 T2DM KARDIOVASZKULÁRIS BETEGSÉG

Teljes kardiovaszkuláris ris kockázat tényezt nyezői Klasszilus rizikótényezők Lpr, PP, PWV, TC, BKI, egfr MAU, CRP?, Hcys?, LDL-C VNY Dohányzás Új kockázati tényezők Metabolikus szindróma HDL-C TNFα Insulin Abdominalis is Obesitas Glu PAI-1 TG IL-6 T2DM K a r d i o m e t a b o l i k u s r i z i k ó KARDIOVASZKULÁRIS BETEGSÉG

Teljes kardiovaszkuláris ris kockázat tényezt nyezői Klasszilus rizikótényezők Lpr, PP, PWV, TC, BKI, egfr MAU, CRP?, Hcys?, LDL-C VNY Dohányzás Új kockázati tényezők Metabolikus szindróma HDL-C TNFα Insulin Abdominalis is Obesitas Glu PAI-1 TG Húgysav IL-6 T2DM K a r d i o m e t a b o l i k u s r i z i k ó KARDIOVASZKULÁRIS BETEGSÉG

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 elhízás inzulin rezisztencia ia + hyperinsulinemia glucose metabolismus ± glucose intolerancia ia húgysav metabolismus húgysav vizelet húgyh gy- sav clearance dyslipidemia TG PP lipemia HDL-C PHLA small dense LDL ApoA1/ApoB hemodynamika SNS aktivita tivitás Na retentio hypertonia Car-Ren-Cer-Vasc Cer-Vasc betegség újabb rizikó faktorok CRP PAI-1 Fibrinogen OSAS

WORLD Attributable Mortality by Selected Leading Risk Factors High Blood Pressure High BMI Number of Deaths (in thousands) IBLF dialogue with WHO.London.28.October.2002

Oki összefüggés s a 10 leggyakoribb kockázati tényező és betegség között Elvesztett életévek

HYPERTONIA

Estimated total number of adults with hypertension Measure Total number worldwide in 2000 n (95% CI) 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 sure 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 p at the start of that decade Lancet.360: 1903.2002

Heart Failure Incidence as a Function of Hypertension Stages 10 8 Annual Rate/1000* Men Woman 6 4 2 0 *Age-adjusted Normal Pre-Hypertension Stage 1 Stage 2 <120/80 120-139/80-89139/80-89 89 140-159/90-99159/90-99 99 160+/100+ Framingham Heart Study 1995

Participating countries Belgium Germany Hungary Italy Netherlands Norway Portugal Slovenia Spain Sweden Turkey UK Kjeldsen SE,, Farsang C, Nadich-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,, Farsang C, Nadich-Brule L, Perlini S, Zidek W. J Hypertens 2008

Participating Countries Latvia Belarus Czech Republic Slovakia Ukraina Romania Bosnia Serbia Albania BP-CARE Study 2008

Concomitant risk factors 100 80 60 (%) 40 59.3 ± 1.4 50.7 ± 2.1 40.4 ± 5.4 39.5 ± 2.9 23.7 ± 2.5 20 15.1 ± 1.1 11.5 ± 1.1 0 TC >200 mg/dl CHD Metabolic Syndrome Obesity Diabetes Smoking Stroke 2.5 ± 0.4 Renal Failure (Cl. Creat.. <60 ml/min) TC = Total Cholesterol; CHD = Coronary Heart Disease. BP-CARE Study 2008

Patients (%) under Monotherapy and Combination Treatment 4.8% 15.3% 19.6% Albania 95.2% Bosnia 84.7% Belarus 80.4% Average value Czech Republic 82.9% 17.1% Latvia 7.8% 92.2% Romania 89.0% 11.0% 13± 1.5% 87±1.5% 15.7% 13.6% 12.4% Serbia 84.3% Slovakia 86.4% Ukraina 87.6% Monotherapy Combination BP-CARE Study 2008

Treated Patients (%) with BP Control 72.9±3.6% 27.1± 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 p<0.001 72.4 77.7 95.3 60 50 40 30 20 10 0 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,, Farsang C, Nadich-Brule L, Perlini S, Zidek W. J Hypertens 2008

25 20 15 10 5 0 7,9 4,1 12,3 9,9 10,2 10,8 8,3 8,2 6,5 5,7 6 4,2 6,3 6,3 4,8 2,7 2,7 2,3 5,1 4,7 7,7 Zala Ország Bács Békés Csongrád Fejér Győr HajdúHeves Jász Komárom Nógrád Pest Somogy Szabolcs Tolna Vas Veszprém % A 130/80 Hgmm célvérnyomás értéket elérők aránya diabeteses betegek (2005) Hypertension Register of Hung. Soc. Hypertens. 2005 % 7.7 Baranya Borsod Budapest

A 130/80 Hgmm célvérnyomás értéket elérők aránya diabeteses betegek (2007) % 25 2007 22,1 20 15 13,5 13,5 13,9 11,8 11,8 10 8,5 7,8 8,3 9,5 8.5 8,5 5 6,2 3,2 5,1 5,4 2,9 2,4 3,6 4,8 0 Baranya Borsod Budapest Bács Békés Csongrád Fejér Győr HajdúHeves Jász Komárom Nógrád PestSomogy Szabolcs Tolna Vas Veszprém Zala % Ország * Nógrád és Heves megyékből 2007-ben nem érkezett adat. Hypertension Register of Hung. Soc. Hypertens.

Blood pressure and risk factors n=534, Correlations are adjusted for sex Hematocrit * * Cholesterol * * * * * Triglycerides * * * * * * * BP * * * * * * * Overweight Tecumseh BP Study, 1990. * * * * Heart Rate * * Diabetes ***p<0.001 **p<0.01 *p<0.05

OBESITAS

Kapcsolat a rizikófaktorok között 6.6 60 mmol/l 6.2 5.8 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 Total cholesterol Triglycerides HDL cholesterol 0 18 20 22 24 26 28 30 32 34 Body Mass Index (kg/m²) Body Mass Index (kg/m²) SBP 50 40 30 20 10 % with high SBP % with high SBP % with high SBP Data from British Regional Heart Survey

6 5 4 3 2 1 0 Obesity and Coronary Heart Disease Mortality Nurses Health Study: Women Who Never Smoked <19 <19 19-21.9 19-21.9 22-24.9 22-24.9 25-26.9 25-26.9 27-28.9 27-28.9 29-31.9 29-31.9 32 32 BMI (kg/m 2 ) p < 0.001 for trend N Engl J Med ;333:677.1995 Relative Risk of Coronary Heart Disease Mortality

Hypertoniás lesz 15 évesen T2 DM t kap 23 évesen Mikroalbuminuriás lesz 32 évesen PROGNÓZIS Első MI:38 éves korában Szívelégtelenség: 41 éves korában Második MI 48 évesen (túléli?)

Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Idiopathic intracranial hypertension Stroke Cataracts Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gout 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 ITT population HDL-C percent change at 1 year (Mean percent change +/- SEM) from baseline Percent change in HDL-C (%) 13 11 9 7 5 3 1-1 -3 Placebo Rimonabant 20 mg 7.37% vs Pbo p<0.0001 Days in the study D-7 D14 D120 D180 D270 D364 LOCF 8.7% 1.8% n 377 388 371 312 285 249 217 377 381 330 307 281 250 388

Change from baseline in small LDL particles (%) ITT, LOCF* (Mean change +/- SEM) from baseline Change in relative proportion of small LDL particles 0-1 -2-3 -4-5 -6-7 -8-9 -10 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 Placebo Rimonabant 20 mg LOCF -2.44 ± 0.86-7.78 ± 0.88-6.46 ± 1.10 vs Pbo p<0.0001 * LOCF excluding data after any change in lipid modifying agents

ADAGIO ITT population TG percent change at 1 year (Mean percent change +/- SEM) from baseline Percent change in Triglycerides (%) Placebo Rimonabant 20 mg 0-2 - 2.7% -4-6 -8-10 -12-17.9% vs Pbo -14 p<0.0001-16 -18-20 - 19.5% -22-24 Days in the study D-7 D14 D120 D180 D270 D364 LOCF n 376 383 368 311 283 248 216 376 376 325 302 277 244 383

Changes in Visceral Fat Area & Subcutaneous Fat Area at 12 months ITT, LOCF* Visceral adipose tissue Mean % change from baseline (SD) Placebo Rimonabant 20 mg n=87 n=92 Subcutaneous adipose tissue Mean % change from baseline (SD) Placebo Rimonabant 20 mg n=72 n=68-5.9 (18.9) - 4.7 (10.0) - 9.7 (10.4) - 16 (17.8) -10.08* (2.76) p=0.0003-5.07* (1.75) p=0.0043 *LS mean difference vs pbo. on percent change - Estimate (SE)

Mean change and mean difference from baseline in ADIPONECTIN at 12 months ITT, LOCF Mean % change from baseline 18.89 (2.65) 23.0 p<0.0001 5.1 Placebo Rimonabant 20 mg n=378 n=382

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 PSYCHIATRIC DISORDERS Any event Suicidal ideation Suicide attempt Acute psychosis Anxiety NERVOUS SYSTEM DISORDERS Any event Dizziness Presyncope Cerebral infarction Placebo n=395 2 1 1 0 0 1 0 0 1 ( 0.5) ( 0.3) ( 0.3) ( 0) ( 0) ( 0.3) ( 0) ( 0) ( 0.3) Rimonabant 20 mg n=404 3 2 1 1 1 2 2 1 0 ( 0.7) ( 0.5) ( 0.2) ( 0.2) ( 0.2) ( 0.5) ( 0.5) ( 0.2) ( 0)

Blood pressure and risk factors n=534, Correlations are adjusted for sex Hematocrit * * Cholesterol * * * * * Triglycerides * * * * * * * BP * * * * * * * Overweight Tecumseh BP Study, 1990. * * * * Heart Rate * * Diabetes ***p<0.001 **p<0.01 *p<0.05

DIABETES

Incidence of diabetes New cases of diabetes UK every 10 min Europe every 40 sec USA every 20 sec Campbell, EASD-HID, 2001

Age-adjusted death rate for men with and without diabetes at initial screening for MRFIT Rate / 10 000 person-years 180 160 140 120 100 80 60 40 20 0 65.91 17.05 DM 6.72 1.75 Non-DM 12.49 4,08 160.13 53.20 CHD Stroke Other CVD All deaths Diabetes Care 1993; 16:434-444 444

CVD Death Rate per 10 4 140 120 100 80 60 40 20 Age-adjusted CVD death rates by presence of number of RF for men screened for MRFIT, with and without diabetes at baseline non diab diab 0 none one only two only all three RF Diabetes Care 1993; 16:434-444 444

FONTOS KÉRDÉS: Mindegyik antidiabeticum egyformán csökkenti-e a szív-érrendszeri kockázatot?

UKPDS: Original and late-follow follow-up relative risk reduction with metformin End point 1997: 1997: Relative risk reduction (%) 1997: p 2007: 2007: Relative risk reduction (%) 2007: p Any diabetes- related 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 Holman RR et al. N Engl J Med 2008;available at: http://www.nejm.org.

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 HF Cardiovascular mortality 1.46 1.59 0.92 1.05 0.79 0.91 1.42 (1.06 1.91) 1.91) 2.09 (1.52 2.88) 2.88) 0.90 (0.63 1.26) 0.02 <0.001 0.53 Singh S et al. JAMA 2007; 298:1189-1195.

Pioglitazone biztonság End point Death, MI, stroke Pioglitazone (n=8554) (%) 4.4 Control (n=7836) (%) 5.7 Hazard ratio 0.82 (0.72 0.94) 0.94) p 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) 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 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 Hematocrit * * Cholesterol * * * * * Triglycerides * * * * * * * BP * * * * * * * Overweight Tecumseh BP Study, 1990. * * * * Heart Rate * * Diabetes ***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 TC Multivariateadjusted RR* HDL-C Multivariateadjusted RR Non-HDL-C Multivariateadjusted RR TC/HDL-C ratio Multivariateadjusted RR 1st 180 1.00 31 1.00 135 1.00 3.76 1.00 2nd >180 200 1.01 >31 38 0.84 >135 156 1.08 >3.76 4.57 0.95 3rd >200 218 1.07 >38 44 0.80 >156 176 1.10 >4.57 5.49 1.42 Halperin RO et al. Hypertension 2006; 47:45-50. 4th >218 243 1.26 >44 53 0.72 >176 201 1.37 >5.49 6.79 1.21 5th >243 1.23 >53 0.68 >201 1.39 >6.79 1.54 p for trend 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.

ILLUMINATE Major results End point Atorvastatin (n=7534), n Atorvastatin + torcetrapib (n=7533), n Hazard ratio (95% CI) p Major CV events 373 464 1.25 (1.09 1.44) 0.001 Deaths 59 93 1.58 (1.14 2.19) 0.006 Barter PJ, et al. N Engl J Med 2007;357:2109-2122

KÖSZÖNÖM FIGYELMÜKET