Metabolic syndrome &CVS

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Metabolic syndrome iclude several risk factors for cardiovascular diseases , in this topic I discuss the relation of elements of metabolic syndrome and cardiovascler diseases.

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Metabolic Syndrome &CVS:

Metabolic Syndrome &CVS Synonymy Definition Prevalence Risk factors of CHD * Central Obesity *Insulin resistance &DM * Atherogenic Dyslipidemia * Endothelial Dysfunction &Microalbuminuria * Hypofibrinolysis * Inflammation Recommendations Medicine-based evidence

Synonymus:

Synonymus The insulin Resistance Syndrome. Dysmetabolic syndrome. Syndrome X ( Reaven 1988). New world syndrome . Cardiovascular Dysmetabolic Syndrome. Plurimetabolic syndrome. Deadly quartet. Diabesity.

Definition:

Definition 1.WHO ( 1999 ). 2.EGIR ( 1999 ). 3.NCEP ( 2001 ). 4.IDF ( 2005 ).

PowerPoint Presentation:

High waist circumference Plus any two of  Triglycerides (  1.7 mmol/L [150 mg/dL]) ‡  HDL cholesterol ‡ Men < 1.0 mmol/L (40 mg/dL) Women < 1.3 mmol/L (50 mg/dL)  Blood pressure  130 / > 85 mm Hg ‡  FPG ( 5.6 mmol/L [100 mg/dL]) , or diabetes IDF criteria of the metabolic syndrome Abdominal obesity: required for diagnosing the metabolic syndrome International Diabetes Federation (2005) ‡ or specific treatment for these conditions

Insulin Resistance Syndrome:

Insulin Resistance Syndrome Dyslipidemia Hypertension Central obesity Hyperglycemia Endothelial dysfunction/ Microalbuminuria Cardiovascular disease Insulin resistance Bjorntorp P. Annals of Medicine 1992; 24 :465–468; Reaven GM. Banting lecture 1988. Diabetes 1988; 37 :1595–1607; Pinkney JH, et al.Diabetes 1977; 46 (Suppl 2):S9–S13; Groop L, Ekstrand A, Forsblom C, et al . Diabetologia 1993; 36 :642–647.

PowerPoint Presentation:

Metabolic Syndrome

INSULIN RESISTANCE SYNDROME:

INSULIN RESISTANCE SYNDROME PRESENT IN AS MANY AS 24% OF US ADULTS

The prevalence of the metabolic syndrome is high in western population:

The prevalence of the metabolic syndrome is high in western population

Prevalence of insulin resistance correlates with increasing number of metabolic disorders:

Prevalence of insulin resistance correlates with increasing number of metabolic disorders n = 888 Metabolic disorders: glucose intolerance, dyslipidemia, hyperuricemia and/or hypertension. P < 0.001 for differences between all categories. Prevalence of insulin resistance (%) 100 0 80 60 40 20 0 1 2 3 4 Number of metabolic disorders

Insulin resistance is closely linked to cardiovascular disease :

Insulin resistance is closely linked to cardiovascular disease Insulin resistance Present in 92% of patient with type 2 diabetes Approximately doubles the risk of a cardiac event Implicated in 47% of CHD event in patients with type 2diabetes

Metabolic Syndrome increases the risk of coronary heart disease:

Metabolic Syndrome increases the risk of coronary heart disease Prevalence of coronary heart disease (%) 30 20 10 NGT IFG/IGT Type 2 diabetes No metabolic syndrome Metabolic syndrome P = 0.04 P = 0.06 P < 0.001 0

PowerPoint Presentation:

Reilly & Rader 2003; Eckel et al 2005 Plaque rupture/thrombosis Cardiovascular events Atherosclerosis Insulin resistance  Tg Metabolic syndrome  HDL  BP Inflammatory markers Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease Adipocyte Monocyte/ macrophage Genetic variation Environmental factors Abdominal obesity Cytokines Adipokines

Central obesity contributes to hyperglycemia:

Central obesity contributes to hyperglycemia Hyperglycemia Liver Glucose output Glucose uptake Free fatty acids Muscle Visceral Fat Insulin Resistance Obesity

Abdominal obesity: a major underlying cause of acute myocardial infarction :

Abdominal obesity: a major underlying cause of acute myocardial infarction Yusuf et al 2004 PAR (%) a a Proportion of MI in the total population attributable to a specific risk factor Abdominal obesity predicts the risk of CVD beyond BMI Cardiometabolic risk factors in the InterHeart Study 0 20 40 60 18 HTN 10 Diabetes 20 Abdom. Obesity 49 Abn Lipids

Fasting hyperinsluinemia significantly increased CVD risk in the VA-HIT study:

Fasting hyperinsluinemia significantly increased CVD risk in the VA-HIT study 1.31 1.

Risk of cardiovascular disease rises as insulin resistance increases:

Risk of cardiovascular disease rises as insulin resistance increases Quintile of HOMA-IR adjusted for age, sex, ethnicity, LDL, triglyceride, HDL, systolic blood pressure, smoking, alcohol consumption, leisure time exercise and waist circumference (median split) Qt 5 Qt 4 Qt 3 Qt 2 0 1 2 3 4 5 Insulin Resistance (HOMA) Odds ratio 8-year risk of cardiovascular outcomes

Insulin resistance is associated with a proatherogenic profile:

Insulin resistance is associated with a proatherogenic profile Insulin resistant & type 2 diabetes Insulin sensitive & type 2 diabetes Triglycerides HDL-cholesterol Systolic blood pressure INCREASED REDUCED NO CHANGE INCREASED NO CHANGE NO CHANGE

Overall 75%of patients with type2 Diabetes die from cardiovascular diseases :

Overall 75% of patients with type2 Diabetes die from cardiovascular diseases

Type 2 diabetes increases the risk of cardiovascular disease:

Rates (per 10,000 person-year) Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking Total CVD CHD Stroke Other CVD 75 50 25 0 Diabetes No diabetes Relative risk 3.0 3.2 2.8 2.3 Type 2 diabetes increases the risk of cardiovascular disease n = 342,815 n = 5,163

The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group:

The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group 36.5% 34.3% 23.8% 21%

Postprandial hyperglycemia is a greater cardiovascular risk factor than elevated fasting glucose levels:

Postprandial hyperglycemia is a greater cardiovascular risk factor than elevated fasting glucose levels Incidence of myocardial infarction (per 1,000 patients) Postprandial blood glucose, P < 0.05 Fasting blood glucose, P = NS n = 1,139 11-year follow-up Glycemic control: Good Borderline Poor FPG (mmol/l): 4.4–6.1  7.8 > 7.8 PPG (mmol/l): 4.4–8.0  10.0 > 10.0 250 0 200 150 100 50

Subjects with diabetes have a risk of CHD comparable to non-diabetic subject with prior MI:

Subjects with diabetes have a risk of CHD comparable to non-diabetic subject with prior MI

Diabetes increases the extent of macrovascular disease:

Incidence of multivessel disease (%) Diabetes increases the extent of macrovascular disease 80 0 60 40 20 No diabetes Diabetes n = 148 n = 923

Good glycemic contorol is not enough:

Good glycemic contorol is not enough ( UKPDS ) GOOD GLYCEMIC CONTOROL Microvascular complication significant reductions Macrovascular complications no significant effect

Intensive glycemic control reduces microvascular complications :

Intensive glycemic control reduces microvascular complications All microvascular endpoints Cataract extraction Retinopathy 25% P = 0.0099 24% P = 0.046 21% P = 0.015 Microalbuminuria 33% P = 0.000054

Disappointing effect of intensive glycemic control on macrovascular complications:

Disappointing effect of intensive glycemic control on macrovascular complications Non-fatal MI Fatal stroke Non-fatal stroke Not significant P = 0.057 Fatal MI -6% Not significant P = 0.63 -21% Not significant P = 0.60 +17% Not significant P = 0.72 +7%

Proportion of diseases attributable to hypertension:

Proportion of diseases attributable to hypertension Disease % attributable to hypertension Myocardial Infarctions Heart failure A . F. Strokes Renal failure 30 – 40 % Up to 50 % Up to 50 % 30 – 40 % 25 – 30 %

‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk:

‘ Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk Diabetes No diabetes CVD death rate (per 10,000 person-year) 250 0 200 150 100 50 Systolic blood pressure (mmHg) < 120 120–139 140–159 160–179 180–199  200

Feature of atherogenic dyslipidemia:

Feature of atherogenic dyslipidemia Atherogenic dyslipidemia is characterized by the following features: ~low HDL-C ~elevated TG ~elevated levels of small dense LDL particles Atherogenic dyslipidemia is commonly found in ~ subjects with type 2diabetes ~subjects with the metabolic syndrome Atherogenic dyslipidemia is commonly associated with apro-thrombotic& pro-inlammatory state

Dyslipidemia is a common feature of type2 diabetes:

Dyslipidemia is a common feature of type2 diabetes The diabetic dyslipidemic profile is characterized by: Reduced HDL Elevated triglycerides A preponderance of atherogenic small ,dense LDL particles

Diabetes and disturbances to lipid subfractions:

Diabetes and disturbances to lipid subfractions Atherogenic, small, dense LDL cholesterol Cardioprotective, lipid-rich, HDL-2 cholesterol Lipid-poor, HDL-3 cholesterol

The inverse relationship between HDL_C and CHD incidence holds also true for non-caucasian populations:

The inverse relationship between HDL_C and CHD incidence holds also true for non-caucasian populations Relative risk of coronary events during 6 year follow up the j-lit cohort

Coronary heart disease and HDL-C ( Framingham heart study ) :

Coronary heart disease and HDL-C ( Framingham heart study )

HDL cholesterol is a consistent predictor of cardiovascular risk:

HDL cholesterol is a consistent predictor of cardiovascular risk The veterans affairs high-density lipoprotein intervention trial (VA-HIT) 6% 31% HDL CHOLESTEROL TRIGLYCERIDES 22% MI or coronary y death Not predictive of outcome

The inverse relationship between HDL_C and CHD incidence holds also true for non-caucasian populations:

The inverse relationship between HDL_C and CHD incidence holds also true for non-caucasian populations Relative risk of coronary events during 6 year follow up the j-lit cohort

The total cholesterol:HDL cholesterol ratio is a powerful predictor of cardiovascular risk:

The total cholesterol:HDL cholesterol ratio is a powerful predictor of cardiovascular risk 8-year incidence of coronary artery disease (%) 35 0 30 25 20 15 10 5 Total cholesterol:HDL-cholesterol ratio Male Female < 3  3–5  5–7  7–9  9

LDL size was related to CHD incidence in the stanford five –city project:

LDL size was related to CHD incidence in the stanford five –city project

Small ,dense LDL increase cardiovascular risk:

Small ,dense LDL increase cardiovascular risk High levels of small, dense LDL are Associated with a 3-fold increased risk of MI

Insulin resistance correlates with endothelial dysfunction:

Insulin resistance correlates with endothelial dysfunction Whole body insulin sensitivity (MCR; ml/kg/min) Insulin/glucose vasodilation (% change in forearm blood flow ratio) 12 0 10 8 6 4 2 -20 60 0 20 40 Diabetes Control Hypertension r = 0.46 P < 0.05 n = 27

C-reactive protein and components of the Insulin Resistance Syndrome:

C-reactive protein and components of the Insulin Resistance Syndrome n = 1,008 Metabolic disorders: dyslipidemia, upper body adiposity, insulin resistance, and hypertension. Adjusted for age, sex, ethnicity and smoking. Mean ± SE Mean log C-reactive protein (SE) 1.6 0 1 2 3 4 Number of metabolic disorders 1.4 1.2 1.0 0.8 0.6 0.4 0.2 P < 0.001 for differences between all categories, except 2 vs. 4 ( P < 0.005) and 3 vs. 4 ( P = not significant) 0

Elevated C-reactive protein predicts cardiovascular disease:

C-reactive protein (range, mg/l) Elevated C-reactive protein predicts cardiovascular disease Relative risk of cardiovascular events (compared with CRP < 1.5 mg/l) 6 0 5 4 3 2 1 < 1.5 1.5–3.7 3.8–7.3 > 7.3 MI or stroke, P = 0.002 for trend Any cardiovascular event, P = 0.001 for trend n = 366 Adjusted for BMI, diabetes, hypertension, hypercholesterolemia, exercise, family history and treatment assignment.

Progression of diabetes is characterized by increasing PAI-1 levels:

Progression of diabetes is characterized by increasing PAI-1 levels Adjusted for age and gender. Mean ± SE. P < 0.001. PAI-1 antigen (ng/ml) 35 30 25 20 15 10 5 Normal glucose tolerance Impaired glucose tolerance Type 2 diabetes P < 0.001 for all comparisons 0

Elevated plasminogen activator inhibitor-1 (PAI-1) predicts cardiovascular disease:

Elevated plasminogen activator inhibitor-1 (PAI-1) predicts cardiovascular disease n = 234 Matched for age and sex. Relative risk of myocardial infarction (compared with PAI-1  5.8 g/l) PAI-1 (range,  g/l) 4 3 2 1  5.8 5.9–7.9 8.0–13.5  13.6 P < 0.002 for trend 0

Cardiovascular mortality correlates with the severity of microalbuminuria:

Cardiovascular mortality correlates with the severity of microalbuminuria n = 2,431 Survival Time (years) 1.0 0.9 0.8 0.7 0.6 0.5 5 0 0.0 < 150 mg/L 150–300 mg/L > 300 mg/L Urinary protein: 2 3 4 6 7 8 1

Management of the metabolic syndrome:

Management of the metabolic syndrome Appropriate and aggressive therapy is essential for reducing patient risk of cardiovascular disease Lifestyle measures should be the first action Pharmacotherapy should have beneficial effects on Glucose intolerance / diabetes Obesity Hypertension Dyslipidemia Ideally, treatment should address all of the components of the syndrome and not the individual components International Diabetes Federation, 1st International Congress on “Prediabetes” and Metabolic Syndrome (2005)

ATP III guidelines and 2004 Update:

ATP III guidelines and 2004 Update

In patients with atherogenic dyslipidemia the incidence of CHD was significantly reduced in the BIP study:

In patients with atherogenic dyslipidemia the incidence of CHD was significantly reduced in the BIP study

Action to control cardiovascular risk in diabetes ( ACCORD ):

Action to control cardiovascular risk in diabetes ( ACCORD ) AIM -to determine whether intensive vs standard intervention can reduce the rate of major cardiovascular events in diabetic patients -glycaemic ,BP and lipid control are involved Study desigen -averagee follow-up of 5.5 years ,multicenter,double blind ,3x2factorial randamized trial -60centers in the us (financed by NHLBI) Patients characteristics - 10000 type 2 diabetic patients(5800randamized to the lipid arm -men &women aged 50-75 years :>55 for caucasians &african american>50 for as/HISP - lipid levels :LDL-C<170mg/dl (4.4mmol/l)HDL-C<50mg/dl(1.3mmol/l)TG<750mg/dl (8.6mmol/;)

Action to control cardiovascular risk in diabetes (ACCORD ):

Action to control cardiovascular risk in diabetes (ACCORD ) Methodology - randomization for glucose control (HBAIC N.=10000) ~ conventional therapy : target 8% ~intensive treatment: target -randomization for LDL-c Control (N=4200) ~conventional treatment with simvastatin: Target<130mg/dl if no CHD;<100mg/dl if CHD Intensive treatment with simvastatin+fenofiberate Target <100mg/dl if no CHD<75ng/dl if CHD -Randomization for control of hypertension (n=4200) ~conventional treatment :target SPB<130 mmhg ~intensive treatment :target SPB<120mmhg Primary endpoint : major CV events (CV deaths ,non fatal ,non fatal strokes) Timing ; study due to complete in2009

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