Post on 08-Mar-2020
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