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Metabola syndromet 2009 bakgrund och behandling

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1 Metabola syndromet 2009 bakgrund och behandling
Malmö den 12 november 2009 Metabola syndromet bakgrund och behandling Peter M Nilsson Avdelningen för medicin Institutionen för kliniska vetenskaper Universitetssjukhuset MAS, Malmö

2 Structure of Inferno There are nine concentric circles in Hell
Hell is geographically divided into Upper Hell and the Lower Hell by the Walls of the Dis Dante: Divine Comedy

3 Circle 3: Gluttony Dante: Divine Comedy
Sin: to give into one’s physical desires to eat and drink regardless of consequences Punishment: To be bloated and mired in filth, while filth rains down from the sky Dante: Divine Comedy

4 Metabola syndromet Arv Livsstil Ökad risk för: Hjärtkärlsjukdomar
diabetes typ 2, kognitiv dysfunktion

5 Kliniska kardiovaskulära händelser som måltavla för prevention
Improving the Prognosis of Patients with Type 2 Diabetes Slide 28. UKPDS: Major Cardiovascular Single Endpoints of Heart Attacks and Stroke. Hjärtinfarkt, ACS Stroke/TIA Clinical outcomes for heart attacks and strokes are worthy of special consideration, as these are the two key cardiovascular complications which influence long-term survival in patients with type 2 diabetes. Är det Metabola syndromet mer användbart för prediktion av kardiovaskulära händelser än dess ingående delkomponenter?

6 Gerald Reaven, Banting Lecture 1988

7 Karl Hitzenberger, Wien, Österrike
Beskrev Metabola syndromet 1921 på basen av studier gjorda 1915/16

8 (1886 – 1975)

9 Cornerstones in the Insulin Resistance Syndrome (IRS)
Glucose visceral obesity hypertension liver steatosis (NASH) endothelial dysfunction Insulin resistance chronic inflammation dyslipidemia Free Fatty Acids Insulin heredity lifestyle (genes)

10 Fetal tillväxt hämning - HT? - DM2? - CVD? - IRS? - MetS? The Barker hypothesis vs. The ”Mis-Match” hypothesis

11 Metabola syndromet 2009 Patofysiologi Epidemiologi
Insulinresistens med kompensatorisk hyperinsulinemi Glukosintolerans Dyslipidemi Bukfetma; adipokiner Defekt fibrinolys SNS aktivering Störd hemoreologi Neuroendokrina rubbningar Inflammatorisk aktivering Adiponektin (lågt) Endoteldysfunktion Epidemiologi Olika utbredning i förhållande till kön, ålder, social och etnisk bakgrund Koppling till lägre social klass Avhängigt mindre hälsosam livsstil Påverkas av kronisk stress och sömnbrist Kan influeras av läkemedelseffekter

12 Patient med Metabolt syndrom - när misstänka detta?
Status: Bukfetma (jfr. IDF-definition 2005), BT  Dålig livsstil: inaktivitet, dålig kost, rökning Anamnes: ex. graviditetsdiabetes, PCO, acantosis nigricans (mörka pigmenteringar i axiller och runt mammiller) Familjehistoria: för DM2 och HT samt CVD Läkemedel: BB +TD i högdos, oselektiva BB, atypiska neuroleptika, m.fl. Lab: IFG, IGT, ALAT , GT , urat , dyslipidemi

13 Metabolic factors associated with CVD in the postprandial state
Endothelial Dysfunction  Platelet activation  Fibrinolytic resistance  Coagulability  Postprandial Glycemia  Postprandial lipemia

14 Inflammationens betydelse
Inflammation är en evolutionärt selekterad mekanism för vävnadsreparation Markörer för inflammation är akuta fasreaktanter i plasma (C-reaktivt protein, fibrinogen, PAI-1 m.fl.) Dessa syntetiseras i levern och kan triggas av cytokiner, fr.a. interleukin 6 (IL-6) Samband föreligger mellan (buk)fetma, insulinresistens och ökade nivåer av cytokiner (IL-1, IL-6, TNF-) Rökning och kroniska infektioner (H. Pylori, C. pneumoniae, CMV, parodontiter?) kan förstärka inflammatoriska svar Vulnerabla aterosklerotiska plack har en ökad inflammatorisk aktivitet - detta kan inducera apoptos

15 Insulin resistance (IR) syndrome of atherogenic
Potential contribution of expanded visceral adipose tissue to the athero-thrombotic proinflammatory profile of abdominally obese patients Glucose Insulin . Thin fibrous cap . Unstable plaque . Impaired fibrinolysis . Increased collagen . Endothelial dysfunction Apo B Insulin resistance (IR) syndrome of atherogenic dyslipidaemia Triglycerides ↓ Adiponectin HL Liver PAI-1 IR? NEFAs IL-6 TNF- Subcutaneous AT Adiponectin Expanded Visceral AT Glucose Once Visceral Adipose Tissue (VAT) is expanded to near capacity, concentrations of non-essential fatty acids (NEFA) increase in the circulation. High NEFA concentrations result in increased fat deposition in liver and skeletal muscle. fatty liver results in hyperlipidemia and hyperproduction and release of TG, Apo B, Glucose and Insulin Impaired NEFA suppression results in elevated PAI-1, interleukins and TNF-alpha that promote athrogenesis This combined with insulin resistance and dislipidemia signifantly elevate the risk of athrogenesis due to endothelial dysfunction, increased collagen, impaired fibrinolysis and thin, unstable placques. X IR LPL NEFAs Skeletal Muscle Després et al. Ann Endocrinol 2001; 61:31-38

16 Olika definitioner av MetS
WHO 1998 EGIR 1999 NCEP-ATPIII 2001 (reviderad 2005) IDF 2005

17 NCEP ATPIII CRITERIA Metabolic Syndrome (2001)
>3 of the following: FPG > 6.1 mmol/L Abdominal obesity: waist circumference > 88 cm (women) or >102 cm (men) Triglycerides ≥ 1.7 mmol/L HDL-chol < 1.16 mmol/L (women) or < 0.91 mmol/L (men) Blood Pressure > 130/85 mm Hg

18 Metabolic Syndrome NCEP-ATPIII: Prevalence Increases With Age
47 million or 23% of US Adults Have Metabolic Syndrome 5 10 15 20 25 30 35 40 45 20-29 30-39 40-49 50-59 60-69 ? 70 Men (n=4265) Women (n=4559) Prevalence, % Metabolic Syndrome—Prevalent and Problematic in the US Currently, approximately 1 in 4 adults in the United States, or 23%, have metabolic syndrome.1 The incidence of metabolic syndrome is comparable to that of hypertension, which is 24%. These statistics may reflect what physicians see in their own clinical practices. The similarity between metabolic syndrome and hypertension in terms of prevalence should lead one to consider an association between the 2 conditions. As the US population ages, the rate of metabolic syndrome steadily increases among men and women in almost all categories of age.1 The prevalence of metabolic syndrome among older segments of the population may approach 50%. At 70 years of age and thereafter, the syndrome plateaus in women and declines in men. In terms of race and ethnicity, Mexican Americans have the highest age-adjusted prevalence of the metabolic syndrome—nearly 32%. Significantly lower rates are seen among whites (24%), African Americans (22%), and people reporting an “other” race or ethnicity (20%).1 Given the prevalence of metabolic syndrome and its strong association with emerging cardiovascular disease and type 2 diabetes, the burden imposed by this syndrome on the US healthcare system is enormous and may seriously strain resources for delivering care as well as escalate cost.1 1. Ford ES, Giles WH, Dieta WH. Prevalence of the metabolic syndrome among US adults. Findings From the Third National Health and Nutrition Examination Survey. JAMA ;287: Age, yr Adapted from: Ford ES, et al. JAMA. 2002;287:

19 Adverse Prognostic Implications of Cardiovascular Metabolic Syndrome
Population-based observational study in 1209 men Metabolic syndrome present Metabolic syndrome absent Coronary heart disease mortality Cardiovascular disease mortality All-cause mortality 5 10 15 20 5 10 15 20 5 10 15 20 RR (95% CI): 3.77 ( ) RR (95% CI): 3.55 ( ) RR (95% CI): 2.43 ( ) Cumulative Hazard (%) Increased rates cardiovascular and all-cause mortality are seen in adults with the metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension. Lakka et al assessed the relationship of the metabolic syndrome with mortality over 12 years in 1,209 Finnish men aged 42 to 60 without cardiovascular disease, cancer, or diabetes at baseline. Unadjusted Kaplan-Meier hazard curves showed significant increases in mortality in men with the metabolic syndrome. Depending on the criteria used for metabolic syndrome, these individuals were 2.9 to to 4.2 times more likely to die of coronary heart disease than men without the syndrome. Risk of cardiovascular disease was 2.6 to 3.0 times higher, and all-cause mortality was 1.9 to 2.1 times higher for men with as opposed to without the metabolic syndrome.1 (Lakka HM, et al. JAMA. 2002;288:Page 2709 abstract) 1. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288: 8 10 12 6 4 2 8 10 12 6 4 2 8 10 12 6 4 2 Follow-up (years) Follow-up (years) Follow-up (years) metabolic syndrome 234 834 100 292 279 288 No 852 866 Yes No. at risk 234 834 100 292 279 288 852 866 234 834 100 292 279 288 852 866 Lakka H-M et al. JAMA. 2002;288:

20 Kritik mot det Metabola syndromet
Bristande precision i begreppet Prediktion av kardiovaskulära händelser kan göras med hjälp av delkomponenter av syndromet – helheten behövs ej! Ej inklusion av variabler som är associerade med insulinresistens, t.ex. markörer för kronisk inflammation Risk för medikalisering av stora befolkningsgrupper med för vida definitioner Avsaknad av riktad medikamentell terapi – men nu finns glitazoner och rimonabant Kahn R, Ferrannini E et al. Diabetes Care 2005;28: Nilsson PM, et al. Diabetic Medicine 2007

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22 Genes and environment in the development of type 2 diabetes and atherosclerosis - CVD
Figure 57 Not much genetic evolution has occurred in humans in the past 20,000 years. In the Palaeolithic age, our ‘thrifty genotype’ was well-adapted to the high level of physical activity associated with our hunter-gatherer existence. However, this genotype has become redundant in the presence of our sedentary lifestyle and a diet low in fibre and high in animal fats and glucides. In short, our genotype – no longer adapted to our lifestyle – has become a ‘susceptibility genotype’. Charles Darwin

23 Key Neurochemical Systems Comprising Brain Reward Circuitry
KoobG/NP/dia1c/021197jh

24 Brain Reward System triggered…

25 …but also by other things!

26 Prevention och behandling av Behandlingspyramiden
Metabola syndromet Behandlingspyramiden Farmaka Livsstils- intervention Motion rökstopp- viktstabilitet/viktreduktion måttligt med alkohol

27 Effekter av motion Fysisk aktivitet HDL Lipider LDL/HDL Tg LDL-K
Blodtryck Fysisk aktivitet Glukos/Insulin Övervikt, bukfetma Trombogenes Direkta effekter på hjärtat Direkta effekter på perifer cirkulation

28 Vältränade överviktiga män löper mindre risk att dö
i hjärtkärlsjukdomar än otränade normalviktiga män Total dödlighet 0,5 1 1,5 2 2,5 3 Smal Normal Övervikt Relativ risk Hjärtkärl dödlighet 1,5 3 4,5 6 7,5 Smal Normal Övervikt Relativ risk Vältränad Otränad Lee CD, Blair ST, Jackson AS. Clin Nutr 1999;69:

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30 Mål för behandlingen Minska den absoluta kardiovaskulära risken associerad med det Metabola syndromet, samt risken för att utveckla typ 2 diabetes hos individer med nedsatt glukostolerans Förbättra livsstil samt livskvalitet Tillämpa svenska riktlinjer från Läkemedelverket samt Socialstyrelsen (Nationella riktlinjer för diabetes och för kranskärlssjukdom), på basen av evidens (bl.a. SBU) LMV. Behandling av typ 2 diabetes, 2003. LMV. Behandling av ateroskleros och hyperlipidemi, 2004 LMV. Prevention av aterosklerotisk hjärtkärlsjukdom 2006

31 SCORE

32 Sammanfattning Hypertoni 2009
Korrekt diagnos - upprepade mätningar Graden av organskada? Kartlägg riskfaktorerna (blodfetter, glukos, rökning, albuminuri) Börja behandla med livsstilsåtgärder, sedan med läkemedel ACE-hämmare, lågdostiazider, kalciumantagonist (amlodipin) är förstahandsmedel - ofta i kombination Andrahandsmedel (?): beta-1 receptor blockerare, angiotensin-2 blockerare PN 2009

33 Blodtrycksläkemedel 2009 EFFEKTER SUBSTANS PROBLEM
ACE-hämmare RAS blockad hosta 15% Lågdos tiazider diures, relaxation gikt, DM2 Kalciumantagonister relaxation ödem Beta-blockerare minskar CO, puls bradykardi, astma Angiotensin-2 blockerare RAS blockad dyra (ännu) CNS medel minskar sympatikus oprövade Läkemedelsboken, Läkartidningen 2008, ESH Guidelines

34 Glitazoner - pros and cons rosiglitazon & pioglitazon
Riktad behandling mot metabol rubbning (IR) Multipla effekter med DM2 prevention (DREAM) Sänker blodtryck något, fr.a. hos IGT patienter Cons Begränsad långtids-dokumentation Hög dygnskostnad Potentiellt allvarliga biverkningar (lever) - dock oftast sällsynta! CAVE! Risk för hjärtsvikt Ridderstråle M, Groop L, Läkartidningen 2002;99:407-10 NEJM 2007, Lancet 2007, N Engl J Med 2007, Lancet 2009

35 Telomeres at the end of the DNA helix

36 Early Vascular Ageing (EVA): MetS, atherosclerosis and arterial stiffening
Foam Cells Fatty Streak Intermediate Lesion Fibrous Plaque Complicated Lesion/Rupture Atheroma Key Points/Summary: Degeneration of healthy endothelium via the pathogenesis of atherosclerosis occurs slowly over decades. It appears to begin with a subtle form of endothelial injury that alters function. Foam cells are the earliest sign of endothelial dysfunction. They are macrophages that contain oxidized LDL-C and are most frequent in infants and children. Foam cells may then infiltrate the vessel, progressing to a fatty streak. As the lesion progresses to an intermediate lesion, small pools of extracellular lipid form within the smooth muscle layers, disrupting the intimal lining of the vessel. Progression to an advanced lesion occurs when the accumulated lipid, cells, and other components of the plaque disrupt the artery wall. This lesion is termed an atheroma. Once the plaque becomes fibrous, it is primed to rupture. This type of advanced lesion can be found from the fourth decade of life onward. The endothelium itself appears to participate in some of this remodeling through secretion of specific compounds. Citation: Butler R, McDonald TM, Struthers AD, Morris AD. The clinical implications of diabetic heart disease. Euro Heart J 1998;19: Endothelial Dysfunction From First Decade From Third Decade From Fourth Decade Smooth Muscle and Collagen Thrombosis Growth of the Lipid Core Nilsson P, Fyhrqvist F, Läkartidningen 2007 Butler R, et al. Eur Heart J 1998;19:

37 Konklusioner Det Metabola syndromet är ett koncept som vuxit fram under de senaste 20 åren, men har rötter tillbaka i observationer från tidigt 1900-tal Insulinresistens förefaller vara en central komponent i detta syndrom En aktuell debatt med kritiska förtecken förs just nu inom vetenskapen gällande definitioner, avgränsningar och behandlingsaspekter på det Metabola syndromet Skattning av absolut kardiovaskulär risk via SCORE och HEARTSCORE bör användas mera PN 2009


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