Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose

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Sviluppo dei farmaci ipoglicemizzanti: metformina, acarbose
Dipartimento
Dipartimento di
di Geriatria
Geriatria ee
Malattie
Malattie del
del Metabolismo
Metabolismo
Seconda
Seconda Università
Università Napoli
Napoli
Sviluppo dei farmaci ipoglicemizzanti:
metformina, acarbose, agonisti
PPAR-γ
Raffaele
Raffaele Marfella
Marfella
52°
52° Congresso
Congresso Nazionale
Nazionale SIGG
SIGG
Firenze,
Firenze, 28
28 novembre
novembre –– 22 dicembre
dicembre 2007
2007
12, 75 – 80, 2006
La prevalenza del diabete mellito
nel mondo aumenterà del 60% passando
dal 4 al 6,4% nei prossimi 20 anni
Diabete e cause di morte
Sobel et Circulation 107:636,2003
28:2 130-2135, 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.
STUDIO
STUDIO MRFIT
MRFIT
Tasso di mortalità da causa cardiovascolare in pazienti di sesso
maschile non diabetici e con diabete noto al momento
dell’arruolamento
90
80
85.13
Tasso di mortalità
(x 10.000 anni/uomo)
70
65.91
60
50
40
30
20
22.88
4.08
4.08
17.05
10
1.75
1.75
0
Tutte
Tutte le
le cause
cause
cardiovascolari
cardiovascolari
Cardiopatia
Cardiopatia
ischemica
ischemica
Non diabetici (n=342815)
Diabetici (n=5163)
6.72
Ictus
Ictus
12.49
Altre
Altre cause
cause
cardiovascolari
cardiovascolari
Stamler J, Diabetes Care 1993
Impact of Diabetes on Cardiovascular Mortality
in MRFIT
Mortality per 10,000
person years
140
120
Diabetic (n=5,163)
91
100
80
59
60
47
31
40
20
0
125
Nondiabetic (n=342,815)
6
12
22
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;434-444. Reprinted with permission from The American Diabetes
Association.
Per each 1% increment in HbA1c, there was an
10% increase in the risk of coronary heart disease
Per each 1% decrement in HbA1c, there was an
16% decrease in the risk of coronary heart disease
Glycemic goals of therapy
to reduce cardiovascular events
Insulin
resistance
Postprandial
glycemia
Beta cell failure
DIABETES
Drugs that may influence
the natural history of diabetes
Insulin
resistance
Post prandial
hyperglycemia
Beta cell
failure
FROM OVERFEEDING TO INSULIN RESISTANCE:
effetcs of PPAR-gamma Agonist and Metformin
Insulin
resistance
Nature Medicine 12, 41 - 42 (2006)
Stressed out about obesity and insulin resistance
Carl de Luca, Jerrold M Olefsky
Thiazolidinediones
Hannele Yki-Järvinen, M.D., F.R.C.P.
Volume 351:1106-1118, 2004
Pharmacotherapy tailored for the
multiple defects of type 2 diabetes
Alpha
glucosidase
inhibitors
Metformin
Insulin resistance
TDZs
FROM INSULIN RESISTANCE TO
POSTPRANDIAL HYPERGLYCEMIA:
EFFECTS OF ACARBOSE
Postprandial
glycemia
Pharmacotherapy tailored for the
multiple defects of type 2 diabetes
Alpha
glucosidase
inhibitors
Metformin
Post prandial
hyperglycemia
TDZs
FROM POSTPRANDIAL HYPERGLYCEMIA TO BETA-CELL FAILURE:
Effects of PPAR-gamma AGONIST, Metformin and Acarbose
Beta cell failure
DIABETES
THE LANCET
Dream Primary Outcome:
Development of Type 2 Diabetes
Pharmacotherapy tailored for the
multiple defects of type 2 diabetes
Alpha
glucosidase
inhibitors
Metformin
Beta-cell survival
TDZs
FROM DIABETES TO CARDIOVASCULAR EVENT:
effetcs of PPAR-gamma Agonist, Metformin and Acarbose
on CVD Risk Factors
Insulin
resistance
Effects of diabetes
on atherosclerotic process
Postprandial
hyperglycemia
Chronic
hyperglycemia
Oxidative stress
Inflammation
Impaired
fibrinolysis
Endothelial
patholgy
Atheroma
Complicated
rupture
Anti-atherosclerotic effects of
PPAR-gamma agonist
Collagen content
%
25,00
20,00
15,00
10,00
5,0 0
8 0 ,0
6 0 ,0
pg/mg
TNF-alpha
*†
4 0 ,0
2 0 ,0
0 ,0
Rosiglitazone
Placebo
Rosiglitazone
Placebo
diabetic
diabetic patients
patientsdiabetic
diabetic patients
patients
Rosiglitazone
Rosiglitazone
diabetic
diabetic patients
patients
Placebo
Placebo
diabetic
diabetic patients
patients
Pharmacotherapy tailored for the
multiple defects of type 2 diabetes
Alpha
glucosidase
inhibitors
Metformin
Cardiovascular
Risk Factors
TDZs
Pathogenesis treatment
Treat earlier
Only 37% of adults 20 years of age
or older have values <7%
of glycosylated hemoglobin