Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose, agonisti

PPAR-γ

Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose, agonisti

PPAR-γRaffaele MarfellaRaffaele Marfella

52° Congresso Nazionale SIGGFirenze, 28 novembre – 2 dicembre 2007

52° Congresso Nazionale SIGGFirenze, 28 novembre – 2 dicembre 2007

Dipartimento di Geriatria e Malattie del Metabolismo Seconda Università Napoli

Dipartimento di Geriatria e Malattie del Metabolismo Seconda Università Napoli

La prevalenza del diabete mellitonel mondo aumenterà del 60% passando

dal 4 al 6,4% nei prossimi 20 anni12, 75 – 80, 2006

Diabete e cause di morte

Sobel et Circulation 107:636,2003

The excess global mortalityattributable to diabetes in the year 2000

was estimated to be 2.9 million deaths, equivalent to 5.2% of all deaths.

28:2 130-2135, 200528:2 130-2135, 2005

STUDIO MRFITSTUDIO MRFIT

0

40

50

60

70

80

90

Tass

o di

mor

talit

à(x

10.

000

anni

/uom

o)

Tutte le cause cardiovascolariTutte le cause

cardiovascolariCardiopatia ischemica

Cardiopatia ischemica IctusIctus Altre cause

cardiovascolariAltre cause

cardiovascolari

20

30

10

Tasso di mortalità da causa cardiovascolare in pazienti di sesso maschile non diabetici e con diabete noto al momento dell’arruolamento

Tasso di mortalità da causa cardiovascolare in pazienti di sesso maschile non diabetici e con diabete noto al momento dell’arruolamento

85.13

22.88

65.91

17.056.721.751.75 12.49

4.084.08

Non diabetici (n=342815)Non diabetici (n=342815)Diabetici (n=5163)Diabetici (n=5163)

Stamler J, Diabetes Care 1993

Impact of Diabetes on Cardiovascular Mortality in MRFIT

MRFIT=Multiple Risk Factor Intervention Trial*Risk factors analyzed: smoking, hypercholesterolemia, and hypertension.

Number of risk factors*

Mo

rtali

t y p

er

10

,00

0

pers

on

ye

ars

Copyright ©1993 American Diabetes Association from Diabetes Care, Vol. 16, 1993;434-444. Reprinted with permission from The American Diabetes Association.

0

20

40

60

80

100

120

140

6

31

12

59

22

91

47

125

None One only Two only All three

Nondiabetic (n=342,815)

Diabetic (n=5,163)

Per each 1% increment in HbA1c, there was an10% increase in the risk of coronary heart disease

Per each 1% decrement in HbA1c, there was an16% decrease in the risk of coronary heart disease

Glycemic goals of therapyto reduce cardiovascular events

Insulinresistance

Postprandialglycemia

Beta cell failureDIABETES

Drugs that may influencethe natural history of diabetes

Insulinresistance

Post prandialhyperglycemia

Beta cellfailure

Insulinresistance

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

Nature Medicine 12, 41 - 42 (2006) Stressed out about obesity and insulin resistance

Carl de Luca, Jerrold M Olefsky

ThiazolidinedionesHannele Yki-Järvinen, M.D., F.R.C.P.

Volume 351:1106-1118, 2004

TDZs

Pharmacotherapy tailored for the multiple defects of type 2 diabetes

Metformin

Insulin resistance

Alphaglucosidase

inhibitors

FROM INSULIN RESISTANCE TOPOSTPRANDIAL HYPERGLYCEMIA:

EFFECTS OF ACARBOSE

Postprandialglycemia

TDZs

Pharmacotherapy tailored for the multiple defects of type 2 diabetes

Metformin

Post prandialhyperglycemia

Alphaglucosidase

inhibitors

FROM POSTPRANDIAL HYPERGLYCEMIA TO BETA-CELL FAILURE: Effects of PPAR-gamma AGONIST, Metformin and Acarbose

Beta cell failureDIABETES

Dream Primary Outcome:Development of Type 2 Diabetes

THE LANCET

TDZs

Pharmacotherapy tailored for the multiple defects of type 2 diabetes

Metformin

Beta-cell survival

Alphaglucosidase

inhibitors

FROM DIABETES TO CARDIOVASCULAR EVENT:effetcs of PPAR-gamma Agonist, Metformin and Acarbose

on CVD Risk Factors

Oxidative stress

Complicatedrupture

Insulinresistance

Postprandialhyperglycemia

Inflammation Impairedfibrinolysis

Effects of diabeteson atherosclerotic process

Endothelialpatholgy

Atheroma

Chronichyperglycemia

Anti-atherosclerotic effects ofPPAR-gamma agonist

Collagen content

TNF-alpha5,00

10,00

15,00

20,00

25,00

0 , 0

2 0 ,0

4 0 ,0

6 0 ,0

8 0 ,0

*†

%

pg/mg

Placebo diabetic patients

Placebo diabetic patients Placebo

diabetic patientsPlacebo

diabetic patientsRosiglitazone

diabetic patientsRosiglitazone

diabetic patientsRosiglitazone

diabetic patientsRosiglitazone

diabetic patients

TDZs

Pharmacotherapy tailored for the multiple defects of type 2 diabetes

Metformin

CardiovascularRisk Factors

Alphaglucosidase

inhibitors

Pathogenesis treatment

Treat earlier

Only 37% of adults 20 years of ageor older have values <7% of glycosylated hemoglobin