Metabolic Syndrome is Related Cardiovascular Disease

Focus : The Role of Metformin on MS

Dr. Pandji Moeljono, Sp.PD-KEMD Spesialis Penyakit Dalam Konsultan Endokrinologi Metabolik dan Diabet RSAL Dr. Ramelan FK. Universitas Hang Tuah Surabaya

Metabolic syndrome Insulin resistance syndrome Dysmetabolic syndrome Cardiometabolic syndrome Dyslipidemic hypertension Hypertriglycerdemic waist The deadly quartet.

Nowadays the name metabolic syndrome is generally accepted.

Krans HM., Insulin Resistence and The Metabolic Syndrome, SUMETSU 3, Surabaya, Februari 2007

Tabel. Definitions of the Metabolic Syndrome

ATP III (American Heart Association) (2005) Minimal requirements Any 3 or mor of the following criteria World Health Organisation 1999 Diabetes, IFG, IGT, or insulin resistance + any 2 or more of the following criteria International Diabetes Federation (2005) Central obesity (see under) + any 2 or more of the following criteria

Waist circumference Waist to hip ratio Reduced HDL cholesterol Elevated Triglycerides Elevated Blood Pressure Urinary Albumin Excretion

In men < 102 cm In women < 88 cm < 0,90 in men < 0,85 in womwn < 1.00 mmol/l in men < 1.30 mmol/l in women > 1.70 mmol/l > 130 / >85 < 0.90 mmol/l in men < 1.00 mmol/l in women > 1.70 mmol/l 140 / 90 > 20 mg/min

In men 94 cm In womwn 80 cm

< 1.03 mmol/l (40 mg/dl) in men < 1.29 mmol/l (50 mg/dl) in women 1.70 mmol/l (150 mg/dl) 130 / 85

Serum glucose

6.1 (5.6) mmol/l

5.6 mmol/l (100 mg/dl)

ATP III (Expert panel etc, 2001) American Heart Association (Grundy et al, 2005) World Health Organisation (World Health Organisation, 1999) International Diabetes Federation (Alberti et al, 2005)

Modified NCEP-ATP III 2001

3 Kriteria dari variabel dibawah ini

1. Lingkar perut
wanita pria 80 cm 90 cm

2. Trigliserida 3. HDLkolesterol
wanita pria

150mg/dL
< 50mg/dL

< 40mg/dL
130/85mmHg 110mg/dL. (sekarang > 100)

4. Tekanan Darah 5. Gula Darah Puasa

METABOLIC SYNDROME THE PREVALENCE

USA NHANES III 1988 1994, of adult population > 20 years, 22.0% or 47 million

Indonesia Clinical setting 2003, of 669 subjects, > 20 years, 35.6% (Adam, Sambo 2003)

Dari 752 DM 58,64% MetS Pria > Wanita = 59% vs 41% (Penelitian di RSAL Dr. Ramelan) (Mulyono P, Perkeni-Makasar, 2005) Penelitian di RSU Dr. Soetomo 60 DM 81,67% Mets (Adi S, Perkeni, 2005

Rural area 2004, of 500 subjects, > 19 years,19.2% (Suastika, 2004) Pre Diabetes 9% and Diabetes 5,2% (n = 5873) (Manaf A, SUMETSU 3, 2007) at Padang Sumatera Barat.

OBESITY is defined as condition in which there is an excess of body fat

The operational of OBESITY and OVERWEIGHT are based on BMI which is correlated closely with body fatness

BODY MASS INDEX (BMI)

Weight (kilogram) Height (meter2) kg m2

Fat distribution in men tend to accumulate in the upper part of the body or in the abdominal region (android obesity), while in women it tends to accumulate in the peripheral part of the body or gluteofemoral region (gynoid obesity)

Android obesity Gynoid obesity

It is a fact that abdominal fat is more insulin resistance than fat from the other parts

 OBESITY AND METABOLIC RISK ABDOMINAL VS. PERIPHERAL OBESITY

Large Insulin-Resistant Adipocytes

Small Insulin-Sensitive Adipocytes

Android Obesity

Gynoid Obesity

"The Cumulative Metabolic Syndrome"

A Cluster of 10 Possible Metabolic and CV Risk Factors (Visceral Obesity is the Culprit)
(Summarized : Tjokroprawiro 2002, 2003)
Visceral Obesity "The Black Goat"

ACTH, Cortisol ( Salivary Cortisol)

1 10

Insulin Resistance 2 Hyperinsulinemia

Hyperuricemia 9
Inflammatory Markers 8 (CRP, TNF, IL - 1, IL - 6) Vascular Abnormalities 7 - Urinary Albumin Excretion - Endothelial Dysfunction

VISCERAL ADIPOSE TISSUE

GABRA-6 ?

IFG IGT

DM

4 Atherogenic Dyslipidemia
Triglycerides HDL-Cholesterol Apolipoprotein-B Small Dense LDL

6 Prothrombotic State
PAI-1 (Esp. Omental Fat) Factor VII Fibrinogen vWF Adhesion Molecules

5 Hypertension LVH CHF

DIABETES vs PRE-DIABETES
Fasting Blood Glucose Normal < 100 * Pre-Diabetes 100 * 125 Diabetes 126 2 hours post prandial (mg/dl) < 140 140 199 200

If FBG is > 100, have a 10-15% chance of developing DM in next 7 years.

ATHEROSCLEROSIS INDUCED BY NON-APPROPRIATE LIFESTYLE

Poor Physical Activity Rich Meal

Visceral Fat Obesity

Abnormal Secretion of Adipocytokines AdiponectinPAI-1

Insulin Resistance
Hyperlipidemia

Diabetes

Hypertension

Atherosclerosis
SUMETSU 2007
YAMATO INSTITUTE OF LIFESTYLE-RELATED DISEASES 070217

UKPDS :
100

Progressive Deterioration of -Cell Function

Beta Cell Function (%)

75
Postprandial Hyperglycemia

Th/Expectation

50
IFG IGT

Facts
T2 DM phase I

T2DM phase III

25

T2DM phase II

-12 10 -6 -2 0 2 Years from Diagnosis

10

14

Modified from Lebovitz H. Diabetes Review 1999;7:139-53

Dual Defect of T2DM (IR and Impaired AIR) : Treating a Moving Target
Insulin Resistance

T2DM

-cell Dysfunction

-Cell Failure Insulin Concentration Insulin Action Euglycaemia Normal IGT+Obesity or IFG Dx T2DM
Progression to T2DM

Perjalanan Alami DM Tipe 2

Sekresi Insulin
Type 2 diabetes IGT Impaired glucose metabolism Normal glucose metabolism 50% 70-100% 150% 100%

Sensitivitas Insulin
30% 50% 70% 100%

Diabetes Obes Metab 1999; 1(1): S1

EFEK RESISTENSI INSULIN

Glucose uptake Glucose oxidation

Insulin resistance

Lipolysis Free fatty acid

Hyperinsulinemia Hyperglycemia Dyslipidemia

Glucose uptake Glucose production VLDL synthesis

Insulin Resistance Hyperinsulinemia

Glucose intolerance

Increased triglyceride

Decreased HDL Cholesterol

Increased blood pressure

Small dense LDL cholesterol

Increased Uric acid

Increased PAI - 1

Coronary heart disease

Pilihan Terapi DM Tipe 2 Berdasarkan Target Organ

HATI PANKREAS
JARINGAN LEMAK OTOT

PRODUKSI GLUKOSA

Biguanides (Metformin) Thiazolidinediones

SEKRESI INSULIN Sulfonylureas

AMBILAN GLUKOSA PERIFER

Meglitinides ; Repaglinide
Insulin

Thiazolidinediones
Biguanides (Metformin)

SAL. CERNA
alpha-glucosidase inhibitors
ABSORBSI GLUKOSA

Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):5515

Obat Anti-hiperglikemia Oral Yang Ideal

Dapat mengontrol gula darah

Tidak ada risiko hipoglikemia

Mempunyai dampak yang menguntungkan pada parameter lipid Aman dan dapat ditoleransi dengan baik Pemberian sederhana

Dapat digunakan oleh semua penderita DM tipe 2

Menurunkan morbiditas/ mortalitas kardiovaskuler dan mikrovaskuler

Exogenous factors Lack of exercise Adiposis

Increased cellular insulin resistance

Impaired rapid insulin secretion

Genetic disposition

Postprandial hyperglycemia Hyperinsulinemia through compensatory other production

Raised blood sugar becomes toxic (glucose toxicity)

Prediabetes

The point of action of oral antidiabetic in the pathophysiology of type 2 diabetes

Increased insulin resistance and decreased insulin secretion Chronic Hyperlgycemia and hyperinsulinemia Further increase in insulin resistance Gradual decrease in insulin secretion

Manifest diabetes

Advanced diabetes

Tabel. Pencegahan DMT2 :

Hasil-Hasil Berbagai Studi Uji Klinik Randomisasi
Penurunan Risiko Relatif (%)
31 46 37

Study Da Qing XENDOS

Intervensi Modifikasi gaya hidup Orlistat

Finnish Diabetes Prevention

Diabetes Prevention Program Diabetes Prevention Program STOP-NIDDM

Modifikasi gaya hidup

Modifikasi gaya hidup Metformin Acarbose

58
58 31 25

TRIPOD
DREAM

Triglitazone
Rosiglitazone

55
62

Syahbudin, Pencegahan Diabetes Mellitus Tipe 2, SUMETSU 3, Surabaya, Februari 2007

Metformin improves endothelial function in patients with metabolic syndrome

C. VITALE1, G. MERCURO2, A. CORNOLDI1, M. FINI1 , M. VOLTERRANI1 & G. M. C. ROSANO1
Journal of Internal Medicine 2005: 258 : 250-256

Background Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA-IR, homeostasis model assessment-insulin resistance),in patients with MS.

Methods.
Sixty-five subjects (37 men and 28 women, mean age 54 6 years) with MS were allocated to receive metformin 500 mg twice daily (n 32) or placebo (n 33) for 3 months. Before and after treatment we assessed endothelial function, using flow-mediated dilatation of the brachial artery, and HOMA-IR.

Results.
Patients who received metformin demonstrated statistically significant improvement in endothelium-dependent vasodilation compared with those treated with placebo (from 7.4 2.1% to 12.4 1.9% vs. 7.3 2.5% to 6.9 2.7%, P 0.0016, metformin vs. placebo respectively), without significant effect on endothelium-independent response to sublingual glyceryl trinitrate (P 0.32).

Metformin improved insulin resistance compared with placebo group (HOMA-IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA-IR, P 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r )0.58, P 0.0016) was found.

Conclusion
Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.

UKPDS: HbA1c in Metformin Study

Median HbA1c (%) 10 9 8

Cross-sectional, Median Values

7
6 0 15 Conventional 0 3 6 9 Years from randomization Glibenclamide 12 Insulin Metformin

Chlorpropamide

UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: FPG in Metformin Study

200 Median FPG (mg/dL) 180

Cross-sectional, Median Values

160
140

120
0 0 15 3 6 9 Years from randomization Glibenclamide 12 Insulin Metformin

Conventional

Chlorpropamide

UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Change in Body Weight in Metformin Study

Cross-sectional, Mean Values
Mean change in weight (kg) 10 7.5 5 2.5 0 Baseline = 85 kg (187 lb) 0 15 3 6 9 Years from randomization 12

2.5 Conventional

Chlorpropamide

Glibenclamide

Insulin

Metformin

UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Plasma Insulin in Metformin Study

10 8 6 4 2 0 -2 -4 -6 Median change in plasma insulin (U/mL)

Cross-sectional, Median Values

Baseline = 16 U/mL 0 15 3 6 9 Years from randomization Glibenclamide 12 Insulin Metformin

Conventional

Chlorpropamide

UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Hypoglycemic Episodes in Metformin Study

Actual Therapy Analysis
Proportion of patients (%)
50 40 30 4

Any episode

Major episodes

20
10 0 0 2 4 6 8 10 2

0 0 2 4 6 8 10

Years from randomization

Conventional Chlorpropamide Glibenclamide Insulin Metformin

UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Myocardial Infarction in Metformin Study

Proportion of patients with events 35% 30% Conventional (n=411) Intensive (n=951) Metformin (n=342) 20% M vs C P=0.01

10% M vs I P=0.12 0 3 6 9 12 Years from randomization 15

0%

UKPDS Group. Lancet. 1998;352:854-865.

CODE-2 (Cost Of Diabetes in Europe Type 2)

CODE-2: summary of results

Mean HbA1c = 7.5%1

Only 31% of individuals achieved good glycemic control (HbA1c 6.5%)1 Only 64% tested for HbA1c within 6 months1 < 50% reached systolic and diastolic blood pressure targets1 Majority had borderline total cholesterol levels (mean = 5.7 mmol/l [220 mg/dl])1 Reduced quality of life associated with:2 insulin use complications
1Liebl

A, et al. Diabetologia 2002; 45:S23S28. 2Koopmanschap M. Diabetologia 2002; 45:S18S22.

CODIC-2 (Cost Of Diabetes In China Type 2)

CODIC-2: prevalence of type 2 diabetes and glycemic control

Prevalence of type 2 diabetes is 4.8% in urban China, but only 30% of this population are diagnosed Of the diagnosed population, only 40% are treated Of > 5,000 patients with type 2 diabetes, 32% had poor glycemic control (HbA1c > 7.5%)
National Bureau of Statistics in China 2001; The Yearbook of Chinas Cities 2000; China Pharmaceutical Report, Vol 7, No. 4; ISIS Diabetic Therapy Monitor, Ph5 & 6.

CODIC-2: percentage of type 2 diabetes complications (macrovascular)

16 14 Patients (%) 12 10 8 6 4 2 0 AMI CHF Angina 2.3% 2.4% 6.5% 12.0% 14.8%

0.2%
CABG

0.5% PTCA Stroke TIA

Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.

CODIC-2: percentage of type 2 diabetes complications (microvascular)

25 20.2% 20 Patients (%) 15 10 5 3.0% 0.3% 21.2%

7.0% 1.5%
Photocoagulation Renal failure

0.4%
Dialysis Peripheral neuropathy

0
Foot ulcer Amputation Blindness

Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.

CODIC-2: effect of complications on cost

45,000
Average annual direct medical cost per patient (RMB)

Direct medical costs (RMB) 46.7

Proportion (%)
935%*

50 45 40 35 30 25 20 15 10
Proportion of patients (%)

40,000 35,000 30,000 25,000 20,000 15,000 10,000

15,373

38,580

22.3
313%* 17.7

218%*
11,842 3,726

13.3

5,000
0

5
0
Macrovascular Both micro- and macrovascular

No complications Microvascular

*Percentage increase in costs vs. no complications

Chen Xingbao, Chinese Health Economics 2003. Tang Ling, China Diabetic Journal 2003.

Lessons from the UKPDS

Too few patients achieved target HbA1c levels, and progression to combination therapy was almost inevitable1
After 3 years of monotherapy, 50% of patients required combination therapy1 Progression of type 2 diabetes was associated with deterioration of glycemic control2

No therapy studied reduced disease progression (until 1999)2

1Turner

RC, et al. JAMA 1999; 281:20052012. 2UK Prospective Diabetes Study. Lancet 1998; 352:837853.

Metformin : Potential Combination with Other Oral Agents

Glipizide Gliclazide Glimepiride Glibenclamide
Acarbose Miglitol Voglibose

Sulphonylureas Glibenclamide

TZDs

Metformin

-Glucosidase Inhibitors

Rosiglitazone Pioglitazone

Meglitinides

Repaglinide Nateglinide

Metformin 21 Metabolic-Cardiovascular Effects

Metabolic Effects
Carbohydrate : 9
1 2 3 4 5 6 7 8 9 Glucose Absorption FBS 2h PP Glycogenesis Insulin Rec. Binding GUT : GLUT-5 Expression Post-Receptor Effect GLP-1 Degradation *) Gluco- and Lipo-toxicity **)

Cardiovascular Effects
Vasoprotective : 9
1 2 3 4 5 6 7 8 9 Hyperinsulinemia Platelet Aggregation Erythrocyte Deformability Fibrinolysis (Fibr.; PAI-1; FVII;FXIIIa) Peripheral A Blood Flow Capillary Permeability Carbonyl Stress SMC-Fibroblast Retinal Neovascular
METFORMIN

Lipid : 3
1 Tot-Chol LDL-Chol 2 TG 3 HDL-Chol

*) GLP-1 Degradation (Mannuci et al 2000) Insulin Secretion **) Prevents B-Cells from Gluco- and Lipo-toxicity (Patane et al 2000)

Rationale Strategy for Metabolic Cardiovascular Care in T2DM

Askandar, SUMETSU, 2007

Metformin with 10 Metabolic-Cardioprotective Effects

IMPROVED
1 2 3 4 5 Insulin Sensitivity Fibrinolysis Nutritive Capillary Flow Hemorrheology Postischemic Flow
6 7 8 9 10

REDUCED
Hypertriglyceridemia AGE-formation Cross-linked Fibrin Neovascularization Oxidative Stress

Reduced Cardiovascular Risk

PIVOTAL ROLES OF METFORMIN Metabolic-Cardiovascular Care in T2DM and the MetS-DM

Metabolic-Cardiovascular Benefits of Metformin

Metformin is more than an Oral Hypoglycemic Agent (Pleiotropic Effects : Metabolic - Cardiovascular Effects) 1 2 3 4 5 6 Antiatherogenic Properties Specific Target on Mitochondrial Metabolism and T2DM Inhibition of Glycation Processes Vascular Protection Prevention of T2DM and CV Complications 10 Pleiotropic Effects of Metformin 21 Metabolic-Cardioprotective Effects of Metformin

MECHANISM OF ACTION METFORMIN

Same Mechanism of Action as GLUMET (Metformin)

LIVER
Decreases Hepatic Glucose Production

MUSCLE INTESTINE
Improves Insulin Sensitivity by Increasing Peripheral Glucose Uptake

Decreases Intestinal Absorption of Glucose