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THE PREVENTION OF TYPE 2 DIABETES MELLITUS. Prof. Dr. Predrag Djordjevic. Diabetes Centre, Institute for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade Serbia and Montenegro. IGT and Macrovascular Complications.

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    1. THE PREVENTION OF TYPE 2 DIABETES MELLITUS Prof. Dr. Predrag Djordjevic Diabetes Centre, Institute for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade Serbia and Montenegro

    2. IGT and Macrovascular Complications IGT as defined by the WHO guidelines (2h-OGTT) is a risk marker for macrovascular complications. 2 known diabetes 1,75 IGT 1,5 IFG Hazard ratio 1,25 1 CVD CHD Stroke All causes Adapted from: DECODE study group: Arch Intern Med 161: 397- 404, 2001.

    3. A) Lifestyle factors a)Dietary issues High fat and low carbohydrate diets have been linked with type diabetes. Vegetable fat and polyunsaturated fat had reduced risk. Trans-fatty acids had increased risk. No increase of risk associated with high saturated fat intakes

    4. Our experiences 2. Dietary Fat Intake as Risk Factor for the Development of Diabetes Multi-Centre Study of the Mediterranean Group for the Study of Diabetes (MGSD) AC. Thanopoulou1, BG. Karamanos1,,.....V. Dimitrijevic4, P. Djordjevic4.....and MTP. Tenconi 9 Diabetes Care 26:302-307, 2003. Summary: We have presented data showing that both subjects with recently diagnosed diabetes and subjects with undiagnosed fasting glycaemia in the diabetic range, compared with matched control subject, have higher intake of fat and especially animal fat. Our data support the view that increased animal fat in diet may contribute to increased incidence of diabetes. Comment: In the present study, fat intake especially of animal origin was strongly associated with both recently diagnosed type 2 diabetes and undiagnosed type 2 diabetes. Increased fat intake effect maybe mediated through changes in insulin sensitivity. Saturated fat is inversely related to insulin sensitivity. Same trend exist for animal fat intake.

    5. Table 2 - Comparison of the energy nutrient intake between subjects with recently diagnosed diabetes, unknown diabetes, impaired fasting glucose and their control groups RDM Control RDM UDM Control UDM IFG Control IFG ----------------------------- 89 ±5 87 ±6 Fat (g/day) 79±2 76 ±2 95 ±6 83 ±6 36 ±3 36 ±3† 31 ±2 Animal fat (g/day) 32 ±1 29 ±1 29 ±2 ----------------------------- 34.7 ±1.5# 30.6 ±1.1 Fat (% of total energy) 30.4 ±1.2 30.2 ±0.5¶ 27.8 ±0.5 32.1 ±1.2 12.5 ±0.7 14.2 ±0.9‡ 10.9 ±0.6 Animal fat (% of total energy) 12.2 ±0.3** 10.8 ±0.3 10.6 ±0.7 ----------------------------- Data are means ± SE. All P values were adjusted for multiple comparison according to Bonferroni † - p=0.043 ¶ - p=0.0001 # - p=0.013

    6. A) Overall, the published information of the effect of lifestyle changes is encouraging, at least a 50% reduction in progression from IGT to type 2 diabetes. However it seems unlikely that significant lifestyle changes will be achieved in many developed countries and or maintained long-term in other vise healthy individuals against a background of unrestrained and relatively unhealthy behavioral lifestyle choices by the rest of community. In this setting, it is important to consider to possibility of pharmacological intervention

    7. Table 3 - Risk factors for type 2 diabetes • Age 45 years • Overweight (BMI  25 kg/m2*) • First degree relative with diabetes • Habitual physical inactivity • Member of a high risk ethnic population (e.g. African-American, Latino, Native American, Asian-American, Pacific Islander) • Previously identified pre-diabetes (IFG or IGT) • History of GDM or delivery of a baby weighing > 9 lbs • Hypertensive ( 140/90 mmHg) • HDL cholesterol level  35 mg/dl (0.9 mmol/l) and/or a triglyceride level  250 mg/dl (2.82 mmol/l) • PCOS • History of vascular disease *May not be correct for all ethnic groups

    8. Prevention strategies A) Lifestyle interventions: a) Diet (reduction of obesity by 10% or more) b) Physical activity (reduction of obesity, increase insulin sensitivity, persistent effects). B) Pharmacological treatment C) Combination: A+B

    9. Fig.1- Proportion of subjects without diabetes during the Trial Cumulative Probability of Remaining Free of Diabetes Tuomilehto J et al. NEMJ 344, 18 May 3, 2001, 1343-50

    10. 8 1y. WHR:-9.4%, -14.4%, -15.1% respectively 2y. WHR:-11.5%, -16.3%, -17.2% respectively Metabolic and function parameters 1 y. Surf. bell. ins. curve: RD -21.2%, ID -32.0%, ID+Ex -33.4% HOMA IR:RD -32%,ID -49.9%,ID+Ex-49.7% HOMA : RD -21.8, ID -36.8%, ID+Ex -37.4 2 y. Surf. bell. ins. curve: RD -28.2%, ID -34.1%, ID+Ex -35.3% HOMA IR:RD -33.5%,ID -51.1%,ID+Ex-50.9% HOMA : RD -22.6, ID -37.0%, ID+Ex -37.5 Reduction of incidence of DM • 1 y. IGT: RD. 48%, ID 56%, ID + Exercise 60% • 2 years IGT: RD. 52%, ID 60%, ID + Exercise 64% Droop out and side effects • 1 year RD 4%, ID 0% ID+Ex 0% • 2 years RD 36% ID 16%ID+Ex 20% CONCLUSION, OBJECTIONS Our results confirmed that in the high-risk subjects with IGT, obesity and older age type 2 diabetes can be prevented by changes in the lifestyle Title of the Study, Authors • BELGRADE DIABETES PREVENTION PROGRAMME, 2000-2003, S&M (former YU) DESIGN Plan of the Study • Randomized • 1. Diet A) Reduction D - RD. B) Individually D. -ID • 2. ID + Exercise - ID+Ex • 3. ID + Ex + Metformin or Placebo • Randomized, double blind, placebo controlled trial (not yet finished) Number of the participants - 125 ? Duration - 3 years Risk factors IGT, Obesity, aged 40-70 years, Intervention measures DIET: 1. RD 1000 kcal/24h 2.ID (aged, sex, BMR, activity level) • For both diet: CH 55-60% fibres 25g/l000 kacl, fats bellow 26%, SAT <8%,PUNS 3-7%, MUNS 11-15% (high CH, high fibre, low fats) 3. Exercise: walking, 1 hour, speed 6km/h daily GOALS • To prevent Type 2DM MAIN RESULTS Weight and anthropometric parameters 1 y. BMI: RD -153%, ID -21.1%, ID+Ex -22.5%, 2y. BMI: RD -19.7%, ID -25.6%, ID+Ex -26.4%,

    11. Normal IGT DM Glucose tolerance after 1 and 2 years 1 year 2 years RD IGT ID IGT ID + Physical activ. IGT

    12. Incidence of Diabetes Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin , p<0.001 vs. Placebo) Risk reduction 31% by metformin 58% by lifestyle The DPP Research Group, NEJM 346:393-403, 2002

    13. Conclusion • T2DM is a preventable disease • Both lifestyle intervention and Metformin were effective in preventing the development of T2DM • Lifestyle intervention was more effective in reducing the risk of T2DM

    14. 11 Reduction of incidence of DM A) The risk of progression to DM over 3.3 years was reduced by 2 5% Acarbose increases the probability that IGT will revert to normal glucose tolerance over time. Weight loss contributed to decreased risk of DM When Acarbose discontinued at the end of the study incidence of DM increased. Droop out and side effects 29.56% of whom 48% during first year Mainly from G I side effects CONCLUSIONS, OBJECTIONS Farmacological intervention with Acarbose could be used either as an alternative or in addition to changes in lifestyle, to delay development of type 2 DM in patients with IGT. Acarbose effectively reduced risk of the developing DM irrespective of age, sex and BMI. 11 patients with IGT would need to be treated for 3-years to prevent 1 case of DM Title of the Study, Authors • STOP NIDDM Study, Multi Nationale (9 Countries), 1996-2001. DESIGN Plan of the Study • Randomized, Double-blind, Placebo-controlled, Multicentric Study • A) Acarbose, B) Placebo Number of the participants - 1429 (714 Acarbose + 715 Placebo) Duration - 3,3 years (Mean follow up) Risk factorsIGT, BMI, 25-40 kg/m2 , High risk population in particular from first degree- relatives of patients with type to DM. Intervention measures FPG: 5.6-7.7 mmol/l. Acarbose 100mg or Placebo, 3 times daly; 3-day nutritional diary phisical activity recorded 3 days GOALS To delay progression from IGT to type 2 DM Primary endpoint: Development of DM MAIN RESULTS Weight and anthropometric parameters Weight: A) 87.6 kg to 87.1 kg (-0.5kg), B) 87.0kg to 87.3 kg (+0.3kg), p=0.018

    15. The Lancet June 2002; vol. 359: 2074

    16. Actual Conclusions • Type 2 DM is a preventable disease • Type 2 diabetes is cardiovascular disease

    17. Effect of Intervention on Metabolic & Risk Factors

    18. Change in Fasting Insulin Change in Insulin (μU/ml)

    19. Change in Blood Presure Diastolic Systolic Change in BP (mmHg)

    20. Change in Lipids Triglycerides Choleterol Change (%)

    21. Conclusion • T2DM is a preventable disease • Both lifestyle intervention and Metformin were effective in preventing the development of T2DM • Lifestyle intervention was more effective in reducing the risk of T2DM • Lifestyle intervention and Metformin were associated with modest improvement in insulinemia and CVD risk factors

    22. Effect of acarbose treatment on the risk of silent myocardial infarction in patients with impaired glucose tolerance: results of randomised STOP-NIDDM trial electrocardiographyUwe Zeymer, A. Schwarzmaier-D’assie, D. Petzinna, JL Chiasson and for the STOP-NIDDM Trial Research GroupEur J Cardiovasc Prev Rehabil 2004; 11:000-000, European Society of Cardiology Beckground The moderate increase in postprandial plasma glucose in subject with impaired glucose tolerance has been shown to be a predictor of cardiovascular disease. In the randomised STOP-NIDDM trial, we could demonstrated that lowering postprandial plasma glucose with acarbose in subjects with impaired oral glucose tolerance could reduced the risk of diabetes. Methods The current report focuses on the effect of acarbose on silent ischaemic events evaluated in the electrocardiographic substudy, using the Minnesota code classification. Results A total of 1181 patients were included in the ECG substudy. From these 72 patients had significant changes between the baseline and end of treatment ECG, 33 in the acarbose and 39 in placebo group. Higher rates of myocardial infarctions occurred in the placebo group (p=0.023 with Chi-square test), while there were no differences between the two groups with ECG changes classified under the other Minnesota codes. Conclusions In this prospective intervention study we could show that acarbose, by decreasing postprandial hyperglycaemia, can reduce the incidence of silent myocardial infarction in subjects with impaired glucose tolerance. This approach should therefore be evaluated in other higher risk populations.

    23. 1st International Congress on ”Prediabetes” and the Metabolic Syndrome Berlin, Germany, April 13-16, 2005. IS IGT DISEASE?METABOLIC PARAMETERS OF ATHEROSCLEROSIS AND THROMBOGENESIS IN MACROANGIOPATHY WHICH ALREDY EXIST Predrag B. Djordjevic, V. Kanjuh, V. Dimitrijevic-Sreckovic, M. Ostojic, S. Popovic, F. Canovic, D. Gostiljac, B. Sreckovic, G. Milic, R. Obrenovic, E. Colak Diabetes Center Institute for Endocrinology, diabetes and metabolic diseases Clinical Center of Serbia Serbia and Montenegro

    24. METHODS • 62 obese patients were included, over 45 years old, with IGT (criteria - WHOWG 1998.) • 48.4% of them was with DMA (CHD, CVD, peripheral artery disease). • Risk factors for atherosclerosis were established: • insulin sensitivity-HOMA IR, insulin secretion-HOMA β, • lipids profile (total, LDL and HDL cholesterol, triglycerides, Apo A and Apo B), • atioxidative protection (SOD, GPX, TAS) • homocysteine-HCS • blood pressure • thrombogenesis: PAI-1 and fibrinogen • Statistical significance between groups with and without DMA was preformed (Students t test).

    25. Lipids P>0.05 p<0.05 6.1±1.6 P<0.05 mmol/L 4.8±1.2 4.7±1.2 3.4±1.2 3.3±0.98 P>0.05 2.1±0.9 1.1±0.37 0.95±0.43

    26. Blood pressure P<0.05 P<0.01 135 ± 24.3 mmHg 95.5 ± 17.8 121 ± 26.2 82.1 ± 12.4

    27. PAI-1 P<0.01 3.8 ± 1.8 1.7 ± 0.9 U/ml

    28. CONCLUSION • Diabetic macroangiopathy exist and is frequent in IGT. It is associated with more frequent presence of risk factors for atherosclerosis and thrombogenesis. • Therefore, IGT is cardiovascular disease, too.

    29. There is growing epidemiological evidence for the association of postprandial hyperglycaemia and macrovascular complications in diabetic patients

    30. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: Meta-analysis of seven long-term studiesH. Hanefeld et al.European Heart Journal 2004; 25: 10-16 Aims • To assess if treatment with the -glucosidase inhibitor acarbose can reduce cardiovascular event in type 2 diabetic patients

    31. Conclusion • Intervention with acarbose can prevent myocardial infarction and cardiovascular disease in type 2 diabetic patients while most of them are already on intensive concomitant cardiovascular medication.

    32. 1st International Congress on ”Prediabetes” and the Metabolic SyndromeBerlin, Germany, April 13-16, 2005. G. Alberti IDF consensus on the metabolic syndrome: DEFINITION AND TREATMENT 2004. • The goal was to find effective but simplest and cheapest parameters

    33. 1. Obesity • BMI • Central obesity (sine qua non) • W/H ratio • W circumference (ethnic specific) 2.  Triglycerides > 1.7 mmol/l (sine qua non) 3. HDL < 0.9 mmol/l - Male < 1.1 mmol/l - Female 4.  Blood Pressure > 130 /  85 mmHg systolic diastolic 5. Dysglicaemia 6. Raised blood glucose > 5.6 mmol/l or preexisting Diabetes mellitus (Gender specific) or Treatment of hypertension Estimation of insulin resistance (IR) is (very) complex one for every day praxis and epidemiological studies because of that we may use following equation : Central obesity + 2 of cited parameters = IR

    34. We need the prospective studies to estimate connection between metabolic syndrome and CVD especially. In the mean time the investigators should be asked to evaluate - sensitivity - specificity - predictivity of all ”new” parameters according its connection with CVD. WHO and perhaps IDF should also be asked to approve any agreed new definition of Metabolic Syndrome

    35. 1st International Congress on ”Prediabetes” and the Metabolic SyndromeBerlin, Germany, April 13-16, 2005. G. Alberti Are We Ready to Treat the Metabolic Syndrome? • Purpose of treatment • To prevent CVD • To prevent type 2 DM • At the moment there is no direct proof that prevention of Metabolic Syndrome means prevention of CVD and DM

    36. According the etiology of Metabolic Syndrome (MSy) treatment measures must be directed to • life style management (amount) • diet • physical activity (increase) • pharmacologic treatment • systematic treatment MSy component • insulin sensitizers (metformin, glitazones) • PPR- and  agonists for glycaemic and lipid disorders • antiobesity drugs - new urgently needed • aspirin • antihypertensives (ACE-I and/or A2 and CB1 receptor blockers) • oral antihyperglycaemic agents • insulin (it will be investigated more precisely) • statin and fibrate • stop smoking • It is unetical not to treat MSy but there is not ”magic bullet” • Finally we do not have specific therapy but we should deal with each of the component abnormalities