Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose, agonisti PPAR-γ

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Renato Romano
6 anni fa
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1 Dipartimento di Geriatria e Malattie del Metabolismo Seconda Università Napoli Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose, agonisti PPAR-γ Raffaele Marfella 52 Congresso Nazionale SIGG Firenze, 28 novembre 2 dicembre 2007

2 12, 75 80, 2006 La prevalenza del diabete mellito nel mondo aumenterà del 60% passando dal 4 al 6,4% nei prossimi 20 anni

3 Diabete e cause di morte Sobel et Circulation 107:636,2003

4 28: , 2005 The excess global mortality attributable to diabetes in the year 2000 was estimated to be 2.9 million deaths, equivalent to 5.2% of all deaths.

5 STUDIO MRFIT Tasso di mortalità da causa cardiovascolare in pazienti di sesso maschile non diabetici e con diabete noto al momento dell arruolamento Tasso di mortalità (x anni/uomo) Tutte le cause cardiovascolari Cardiopatia ischemica Ictus Altre cause cardiovascolari Non diabetici (n=342815) Diabetici (n=5163) Stamler J, Diabetes Care 1993

Impact of Diabetes on Cardiovascular Mortality in MRFIT Mortality per 10,000 person years 140 120 100 80 60 40 20 0 Nondiabetic (n=342,815) Diabetic (n=5,163) 6 31 None One only Two only All three

6 Impact of Diabetes on Cardiovascular Mortality in MRFIT Mortality per 10,000 person years Nondiabetic (n=342,815) Diabetic (n=5,163) 6 31 None One only Two only All three Number of risk factors* MRFIT=Multiple Risk Factor Intervention Trial *Risk factors analyzed: smoking, hypercholesterolemia, and hypertension Copyright 1993 American Diabetes Association from Diabetes Care, Vol. 16, 1993; Reprinted with permission from The American Diabetes Association

7 Per each 1% increment in HbA 1c, there was an 10% increase in the risk of coronary heart disease

8 Per each 1% decrement in HbA 1c, there was an 16% decrease in the risk of coronary heart disease

9 Glycemic goals of therapy to reduce cardiovascular events

13 Insulin resistance Postprandial glycemia Beta cell failure DIABETES

14 Drugs that may influence the natural history of diabetes Insulin resistance Post prandial hyperglycemia Beta cell failure

15 FROM OVERFEEDING TO INSULIN RESISTANCE: effetcs of PPAR-gamma Agonist and Metformin Insulin resistance

16 Nature Medicine 12, (2006) Stressed out about obesity and insulin resistance Carl de Luca, Jerrold M Olefsky

17 Thiazolidinediones Hannele Yki-Järvinen, M.D., F.R.C.P. Volume 351: , 2004

22 Pharmacotherapy tailored for the multiple defects of type 2 diabetes Alpha glucosidase inhibitors Metformin Insulin resistance TDZs

23 FROM INSULIN RESISTANCE TO POSTPRANDIAL HYPERGLYCEMIA: EFFECTS OF ACARBOSE Postprandial glycemia

28 Pharmacotherapy tailored for the multiple defects of type 2 diabetes Alpha glucosidase inhibitors Post prandial hyperglycemia Metformin TDZs

29 FROM POSTPRANDIAL HYPERGLYCEMIA TO BETA-CELL FAILURE: Effects of PPAR-gamma AGONIST, Metformin and Acarbose Beta cell failure DIABETES

32 THE LANCET Dream Primary Outcome: Development of Type 2 Diabetes

35 Pharmacotherapy tailored for the multiple defects of type 2 diabetes Alpha glucosidase inhibitors Metformin Beta-cell survival TDZs

37 FROM DIABETES TO CARDIOVASCULAR EVENT: effetcs of PPAR-gamma Agonist, Metformin and Acarbose on CVD Risk Factors

38 Insulin resistance Effects of diabetes on atherosclerotic process Postprandial hyperglycemia Chronic hyperglycemia Oxidative stress Endothelial patholgy Inflammation Atheroma Impaired fibrinolysis Complicated rupture

39 Anti-atherosclerotic effects of PPAR-gamma agonist

40 Collagen content 25,00 % 20,00 15,00 10,00 5,00 80,0 60,0 pg/mg * TNF-alpha 40,0 20,0 0,0 Rosiglitazone Placebo diabetic patients diabetic patients Rosiglitazone diabetic patients Placebo diabetic patients

43 Pharmacotherapy tailored for the multiple defects of type 2 diabetes Alpha glucosidase inhibitors Cardiovascular Risk Factors Metformin TDZs

45 Treat earlier Pathogenesis treatment

46 Only 37% of adults 20 years of age or older have values <7% of glycosylated hemoglobin

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