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Terapia ipoglicemizzante Terapia ipoglicemizzante
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Trials clinici fondamentali
Intensive blood-glucose control with sulphonlureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).UK Prospective Diabetes Study Group. Lancet 1998; 352:837-53
UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)
DIABETE TIPO 2
Trattamento intensivo: -25% rischio di complicanze microvascolari
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Obiettivi terapeutici Obiettivi terapeutici
GLICEMIA A DIGIUNO
GLICEMIA POSTPRANDIALE
EMOGLOBINA GLICATA
GLICEMIA A DIGIUNO
GLICEMIA POSTPRANDIALE
EMOGLOBINA GLICATA
80-120
100-140
< 6,5%
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Atteggiamento vs diabete
Atteggiamento vs diabete INTERVENIRE SU ABITUDINI VITA
- Suggerimenti nutrizionali - Calo ponderale - Esercizio fisico - Astensione dal fumo
MIGLIORARE GLI ALTRI PARAMETR METABOLICI - Riduzione dei lipidi - Riduzione della PA
FARMACI IPOGLICEMIZZANTI ORALI - Secretagoghi - Insulino-sensibilizzanti
TERAPIA INSULINICA
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Fisiopatologia diabete Fisiopatologia diabete
Condizioni fondamentali per sviluppo di diabete
DEFICIT AZIONE INSULINICA + DEFICIT SECREZIONE INSULINICA
Meccanismi su cui agiscono ipoglicemizzanti orali
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Ridurre l’insulino-resistenza (fegato/rene, muscolo scheletrico, tessuto adiposo)
Ristabilire un appropriato profilo insulinemico (sufficiente secrezione basale e appropriata secrezione post-prandiale, specialmente nelle fasi più precoci susseguenti un pasto)
Contrastare la lipotossicità
Ridurre la glucotossicità
Ridurre l’insulino-resistenza (fegato/rene, muscolo scheletrico, tessuto adiposo)
Ristabilire un appropriato profilo insulinemico (sufficiente secrezione basale e appropriata secrezione post-prandiale, specialmente nelle fasi più precoci susseguenti un pasto)
Contrastare la lipotossicità
Ridurre la glucotossicità
Gli obiettivi fisiopatologici della terapia del diabete di Tipo 2
Gli obiettivi fisiopatologici della terapia del diabete di Tipo 2
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Ridotta utilizzazioneRidotta utilizzazione del glucosiodel glucosio
Aumentata produzioneAumentata produzioneglucosioglucosio
Fisiopatologia diabeteFisiopatologia diabete
Alterata secrezione insulinica
SECRETAGOGHI
FARMACI CHE RIDUCONO INSULINO-RESISTENZA
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Iperglicemia a digiuno
Fisiopatologia diabeteFisiopatologia diabete
Legata soprattutto ad aumento produzione epatica di glucosio
glucosio
insulina
Iperglicemia postprandiale
glucosio
glucosioLegata ad alterata soppressione Insulino-mediata) della produzioneEpatica glucosio+ ridotta utilizzazione(insulinostimolata) del glucosio da Parte del muscolo.
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SECRETAGOGHI
• principale sito d’azione: pancreas
• meccanismo: stimolano il pancreas a
secernere più insulina
• classi: a) sulfoniluree
b) derivati dalla meglitinide
c) derivati dalla D-fenilalanina
d) incretino-mimetici
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• Glibenclamide (Euglucon 5-Daonil)
• Gliclazide (Diamicron-Diabrezide)
• Glimepiride (Amaryl- Solosa)
• Glipizide (Minidiab)
• Repaglinide (Novonorm)
• Nateglinide (Starlix non presente in Italia)
Ipoglicemizzanti orali cheIpoglicemizzanti orali chestimolano la secrezione insulinicastimolano la secrezione insulinica
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ATP-sensitiveATP-sensitive
K channelK channel++
voltagevoltage-dependentdependentCa channelCa channel 2+2+
membranemembranepotentialpotential
CaCa 2+2+
ATP/ADPATP/ADP
insulininsulin
glucoseglucose
Ca -dependentCa -dependent
K channelK channel
2+2+
++metabolismmetabolism
insulininsulingranulesgranules 11
44
Beta cell insulin secretionBeta cell insulin secretion
e-
22
33
Sulfoniluree
Sur 1Kir 1
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farmaco
2. Sito ed affinità di legame
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
5. Tempo di permanenza
del farmaco in circolo
farmaco
Potassium channels
K+
Ca++Ca++
-cell
Insulin secretion
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
3. Interazione con la cellula
Fattori che influenzano lostimolo farmacologico della
secrezione insulinica
1. Farmacocinetica
farmaco
4. Durata del legame
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Cinetica della attivazione (T1/2-on) e della disattivazione (T1/2-off) dei canali del K ATP-dipendenti
T 1
/2
(min
ute
s)
0
40
80
120
160
200
Nateglinide Repaglinide Glyburide Glimepiride
T1/2-on
T1/2-off
Weaver ML et al. Drug Metab Dispos 2001;29:415–21
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farmaco
2. Sito ed affinità di legame
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
5. Tempo di permanenza
del farmaco in circolo
farmaco
Potassium channels
K+
Ca++Ca++
-cell
Insulin secretion
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
3. Interazione con la cellula
Fattori che influenzano lostimolo farmacologico della
secrezione insulinica
1. Farmacocinetica
farmaco
4. Durata del legame
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farmaco
2. Sito ed affinità di legame
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
4. Tempo di permanenza
del farmaco in circolo
farmaco
Potassium channels
K+
Ca++Ca++
-cell
Insulin secretion
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
farmaco
3. Durata del legame
GLIMEPIRIDEGLICLAZIDE MR
1. Biodisponibilità
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farmaco
2. Sito ed affinità di legame
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
4. Tempo di permanenza
del farmaco in circolo
farmaco
Potassium channels
K+
Ca++Ca++
-cell
Insulin secretion
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
farmaco
3. Durata del legame
GLINIDI
1. Biodisponibilità
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Durata d’azione
Tolbutamide
Gliclazide
Glibenclamide
12 hours
< 24 hours
12–24 hours
Repaglinide32 minutes
3–5 hours
Nateglinide 45 minutes2–3 h
Gliclazide MR< 24 hours
12–24 hours
Chlorpropamide 24–72 hours
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Sulfoniluree/Glinidi: quali le differenze ?
- Emivita lunga - Crisi ipoglicemiche- Non riproducono la secrezione fisiologica - Rischi cardiovascolari- Effetto su glicemia a digiuno
- Emivita breve e rapida insorgenza azione- Meno crisi ipoglicemiche- Riproducono meglio la secrezione fisiologica- Minori Rischi cardiovascolari- Effetto su glicemia postprandiale
Sulfoniluree Glinidi
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Diabete mellito di tipo 2: fase precoce della secrezione insulinica nel soggetto sano e nel paziente
diabetico
Ward WK, et al. Diabetes Care 1984;7:491–502.
Soggetto sano Diabetico di tipo 2
120
100
80
60
40
20
0–30 0 30 60 90 120
Tempo (minuti)
–30 0 30 60 90 120
Tempo (minuti)
IRI
pla
smat
ica
(µ
U/m
l)
120
100
80
60
40
20
0IR
I p
lasm
atic
a (µ
U/m
l)
20 g glucosio20 g
glucosio
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Fisiologia del periodo post-prandialeFisiologia del periodo post-prandiale
Rapido e marcato aumento della insulinemia
glucosio Captazione ed utilizzazione del glucosio
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24018060 1200
0
5
15
10
Insu
lin s
ecre
tio
nIn
sulin
sec
reti
on
(
pm
ol/k
g/m
in)
(pm
ol/k
g/m
in)
glibenclamide (5.0 mg)
Rx
-15
repaglinide (1.0 mg )
placebo
Time (min)Owens et al, 1999
Repaglinide: ‘Early’ insulin secretionRepaglinide: ‘Early’ insulin secretion
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Effetto della nateglinide in soggetti con Diabete Tipo 2
300
250
200
150
100
50
0
–50
In
suli
na
(pm
ol/
l)
Tempo (ore)0 1 2 3 4 5 6 7 8 9 10 11 12
Glibenclamide 10 mg (n=50)
Nateglinide 120 mg (n=51)Placebo (n=51)
Hollander PA et al. Diabetes 2001
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Pancreatic -cells / SUR1
Cardiac muscle / SUR2A
Vascular smooth muscle/ SUR2B
Physiologicalstimulus
Hyperglycemia Close channelsin T2D
Open channelsin IHD
Open channelsin IHDneurotransmitters
TherapeuticgoalTissue/receptors
Response
Muscle relaxation
Vasodilatation
Insulin secretion
Shorten action potential
Cardiac workHypoxia
Hypoxia
KKATPATP channel roles and distribution channel roles and distribution
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SulfonilureeSulfoniluree
Farmaci di seconda linea in aggiunta alla metformina quando non si raggiungel’obiettivo di HbA1cPrevalente iperglicemia a digiuno
Insufficienza epatica
Insufficienza renale (si Glimeripide in forme lievi/moderate)
UTILIZZO
CONTROINDICAZIONI
IPOGLICEMIA
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GLINIDI GLINIDI
Farmaci di seconda linea in aggiunta alla metformina quando non si raggiungel’obiettivo di HbA1cPrevalente iperglicemia postprand.Anche in pz con lieve/moderata IRC
Insufficienza epatica
Grave insufficienza renale (si in forme lievi/moderate)
UTILIZZO
CONTROINDICAZIONI
IPOGLICEMIA
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principale sito d’azione: fegato, muscolo tessuto adiposo
classi: - biguanidi: metformina e fenforminafenformina
- glitazoni
Farmaci che migliorano la sensibilità insulinicaFarmaci che migliorano la sensibilità insulinicaFarmaci che migliorano la sensibilità insulinicaFarmaci che migliorano la sensibilità insulinica
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MetforminaMetformina
migliora la sensibilità insulinica dei tessuti periferici bersaglio dell’ormone:
fegato, muscolo, tessuto adiposo
In particolare a livello epatico riducela produzione epatica di glucosio,
inibendo la gluconeogenesi
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Fisiopatologia dell’iperglicemia a digiuno
Insulino-resistenza a livello epatico
insulina
glucosioglucosio
insulina
metformina
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Trials clinici fondamentaliTrials clinici fondamentali
Effect of intensive blood-glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). (UKPDS 33).UK Prospective Diabetes Study Group. Lancet 1998; 352:854-63
UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)
METFORMINA
-42% mortalità per diabete -39% rischio infarto -41% rischio stroke
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METFORMINAMETFORMINA
Prima scelta in Diabete tipo 2Obesi e Sindrome Metabolica.Iperglicemia digiunoIn associazione con tutti gli OHA
Insufficienza epaticaInsufficienza renaleCondizioni di ipossiaCondizioni di ipossia: Insufficienza respiratoria Scompenso cardiaco
UTILIZZO
CONTROINDICAZIONI
Acidosi lattica in 90% dei casi
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GlitazoniGlitazoni
migliorano la sensibilità insulinica dei tessuti periferici bersaglio dell’ormone:
fegato, muscolo, tesuto adiposo
In particolare a livello di muscolo e tessuto adiposo, aumentail trasporto di glucosio, all’interno delle cellule
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Effetti dei TiazolidinedioniEffetti dei Tiazolidinedioni
•Agonisti dei PPR gamma, fattori di Agonisti dei PPR gamma, fattori di trascrizione nucleare che favoriscono la trascrizione nucleare che favoriscono la differenziazione dei fibroblasti in piccoli differenziazione dei fibroblasti in piccoli adipociti più sensibili all’azione adipociti più sensibili all’azione dell’insulinadell’insulina
•Agonisti dei PPR gamma, fattori di Agonisti dei PPR gamma, fattori di trascrizione nucleare che favoriscono la trascrizione nucleare che favoriscono la differenziazione dei fibroblasti in piccoli differenziazione dei fibroblasti in piccoli adipociti più sensibili all’azione adipociti più sensibili all’azione dell’insulinadell’insulina
captazione del glucosiocaptazione del glucosiodella lipolisidella lipolisiconcentrazione plasmatica di concentrazione plasmatica di FFAFFA
captazione del glucosiocaptazione del glucosiodella lipolisidella lipolisiconcentrazione plasmatica di concentrazione plasmatica di FFAFFA
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Effetti dei TiazolidinedioniEffetti dei Tiazolidinedioni
•Stimolano la sintesi di Stimolano la sintesi di GLUT4GLUT4•Stimolano la sintesi di Stimolano la sintesi di GLUT4GLUT4
utilizzazione del utilizzazione del glucosioglucosio utilizzazione del utilizzazione del glucosioglucosio
•Riducono la Riducono la neoglucogenesi perneoglucogenesi per
• minore disponibilità di FFAminore disponibilità di FFA
•Riducono la Riducono la neoglucogenesi perneoglucogenesi per
• minore disponibilità di FFAminore disponibilità di FFA
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GLITAZONIGLITAZONI
Diabete tipo 2 con prevalente insulino-resistenzaIperglicemia post-prandiale (con moderata glicemia a digiuno)MonoterapiaAssociazione con Metformina (quando Met inefficace)Associazione con SU (se intolleranza metformina)
Insufficienza epatica (non iniziare se ALT >2.5 v.n.)Scompenso cardiaco( > ritenzione idrica )Associazione insulina
UTILIZZO
CONTROINDICAZIONI
Aumento di pesoEdema periferico
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Inibitori -glicosidasi intestinaleInibitori -glicosidasi intestinale
Inibisce azione enzimi deputati scissione carboidrati complessi in semplice
Riduce glicemia post-prandiale in misura proporzionale in dieta quantità carboidrati
ACARBOSE
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Effetti gastrointestinali
Inibitori a-glicosidasi intestinale
Ernia iataleGravidanza ed allettamento
UTILIZZO
CONTROINDICAZIONI
In associazione altri ipoglicemizzanti (insulina)quando necessario correggere persistente iperglicemia postprandiale
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La famiglia delle incretine
Analogo del GLP-1 umano, es. liraglutide
Terapie exendin-based, es. exenatide
Agonisti del recettore del
GLP-1
Inibitori di DPP-4, es. sitagliptin, vildagliptin
Terapie incretiniche
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PROGLUCAGONE
GLP-1
• prodotto da cell. L della mucosa della parte distale del piccolo intestino e colon
• secreto in risposta ad ingestione di carboidrati e lipidi
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The Multiple Actions of GLP-1
CNS: promotes satiety and reduction of appetite
Stomach: slows gastric emptying
Beta cell:stimulates glucose-dependent insulin secretioninceases gene expression of key beat cell genesincreases beta-cell mass (in animal models)
Alpha cell:inhibits glucagon secretion
Liver:reduces hepatic glucose
output by inhibiting alpha cell secretion of glucagon
Flint A et al. J Clin Invest. 1998;101:515-520 Larsson H et al. Acta Physiol Scand. 1997;160:413-422Nauck MA et al., Diabetologia 1996, 1546-1553Drucker DJ. Diabetes. 1998;47:159–169.
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ATP
[Ca 2+]
MitochondrialMetabolism
+
-
-
K +
Ca 2+
Sulfonylureas
Gs
GLP-1
PKA
cAMP
Potentiator
Trigger
Insulin
stores
[Ca 2+]
Glucose
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Native GLP-1 is rapidly degraded Human ileum, GLP-1 producingL-cells
Capillaries,Di-Peptidyl Peptidase-IV(DPP-IV)
Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in the human ileum
GLP-1 is a substratefor neutral endopeptidase
(NEP) that has a preferencefor smaller peptides
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GLP-I1. Aumenta la produzione e la secrezione
insulinica in risposta al glucosio, in modo strettamente dose-dipendente
2. Riduce la secrezione di glucagone, rallenta lo svuotamento gastrico e induce sazietà
3. Effetto “autolimitante” quando la glicemia si normalizza
4. Emivita breve (2-5 min); necessità di analoghi ad azione prolungata
(esendina, in sperimentazione)
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Effects of GLP-1 on Βeta Cells
• Acute:Acute:– Enhances glucose-dependent insulin secretionEnhances glucose-dependent insulin secretion
• Subacute*:Subacute*:– Stimulates transcription of proinsulin and Stimulates transcription of proinsulin and
biosynthesisbiosynthesisof insulinof insulin
– Increases expressions of Glut-2 and glucokinaseIncreases expressions of Glut-2 and glucokinase• Chronic*:Chronic*:
– Stimulates proliferation and neogenesis of beta cells Stimulates proliferation and neogenesis of beta cells from precursor ductal cellsfrom precursor ductal cells
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What is known about GLP-1 receptor agonists and DPP-4 inhibitors
• GLP-1 receptor agonists– Pure GLP-1 effect
– Pharmacological levels of GLP-1
– Not limited by endogenous secretion
– Enhanced efficacy
– Some nausea
– Weight loss
– Injection
• DPP-4 inhibitors– GLP-1 and GIP enhanced
– Increased levels of GLP-1 in physiological range
– Limited by endogenous secretion
– Moderate efficacy
– Well tolerated
– No weight change
– Oral
GIP, gastric inhibitory peptide
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Glu Gly PheThr Thr Ser AspVal Ser SerAlaHis Tyr Leu Glu Gly Gln Ala Ala Arg GlyPhe Ile TrpAla Leu Val Lys GlyGluLys
Glu Gly PheThr Thr Ser AspVal Ser SerAlaHis Tyr Leu Glu Gly Gln Ala Ala Arg GlyPhe Ile TrpAla Leu Val Arg GlyGluLys
Glu Gly PheThr Thr Ser Asp Val Ser SerD-AlaHis Tyr Leu Glu Gly Gln Ala Ala ArgLysPhe Ile TrpAla Leu Val Lys GlyGluLys
Glu Gly PheThr Thr Ser AspLeu Ser LysGlyHis GlnMetGlu Glu Glu Ala Val Gly ProPhe Ile TrpGlu Leu Lys AsnGlyLeuArg
Glu
Glu Gly PheThr Thr Ser AspVal Ser SerAlaHis Tyr Leu Glu Gly Gln Ala Ala ArgPhe Ile TrpAla Leu Val Lys GlyGluLys amide
Albumin
GLP-1
(7-36)amide
Liraglutide (NN2211; NovoNordisk)
Pro SerSerSer Gly Ala Pro Pro Amide
amide
OO
OHN
O
N
O
O
CJC-1131 (Conjuchem)
Albumin
Exenatide (Exendin-4/AC2993, Amylin Pharmaceuticals/Eli Lilly & Co. )
(7-37)
MPA
C-16 fatty acid (non-covalent binding to albumin)
Site of proteolytic inactivation (DPP IV)
Lys-AEEA linkerChemical reactant (covalent binding to albumin)
Glycine-extended form
7 302520
77
1510 35 36
37
GLP-1 analogs
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Exenatide augments first- and second-phase Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose insulin secretion in response to intravenous glucose
in subjects with type 2 diabetesin subjects with type 2 diabetes
Fehse F, J Clin Endocrinol Metab. 2005 Nov
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Nathan DM, et al. Diabetes Care 2008;31(12):1-11.
Consensus Statement ADA/EASD 2009:Consensus Statement ADA/EASD 2009:Algoritmo terapeutico del DMT2Algoritmo terapeutico del DMT2
Diagnosis:
Lifestyle+
Metformin
Lifestyle + Metformin+
Basal insulin
Lifestyle + Metformin+
Sulfonylurea
Lifestyle + Metformin+
Intensive insulin
Step 1 Step 2 Step 3
Lifestyle + Metformin+
Pioglitazone (No hypoglycemia /edema (CHF)/ bone loss)
Tier 1Tier 1: well validated core therapies: well validated core therapies
Tier 2Tier 2: Less well validated core therapies: Less well validated core therapies
Lifestyle + Metformin+
GLP-1 agonist b
(no hypoglycemia/weight loss /nausea/vomiting )
Lifestyle + Metformin+
Pioglitazone +
Sulfonylurea a
Lifestyle + Metformin+
Basal Insulin
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GLINIDI:Prandial Glucose Regulators
- Riproducono meglio la secrezione fisiologica - Emivita breve - Meno crisi ipoglicemiche- Minori Rischi cardiovascolari
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24018060 1200
0
5
15
10
Insu
lin s
ecre
tio
nIn
sulin
sec
reti
on
(
pm
ol/k
g/m
in)
(pm
ol/k
g/m
in)
glibenclamide (5.0 mg)
Rx
-15
repaglinide (1.0 mg )
placebo
Time (min)Owens et al, 1999
Repaglinide: ‘Early’ insulin secretionRepaglinide: ‘Early’ insulin secretion
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Glicemia delle 24 h nel soggetto sano e nel paziente diabetico
500
400
300
200
100
0800 1000 1200 1400 1600 1800 2000 2200 0000 0200 0400 0600 0800
Gli
cem
ia (
mg
/dl)
Tempo (ore)
Pasto
PPG
Pasto Pasto
GLINIDI: Farmaci indicati per ridurre i picchi glicemici post-prandiali (PGR)Farmaci a breve durata d’azione
Non-diabetico
Diabete tipo 2 scompensato
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SECRETAGOGHI
• principale sito d’azione: pancreas
• meccanismo: stimolano il pancreas a
secernere più insulina
• classi: sulfoniluree
1) clorpropamide, tolbutamide
2) glibenclamide, gliclazide
3) glimepiride
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farmaco
2. Sito ed affinità di legame
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
4. Tempo di permanenza
del farmaco in circolo
farmaco
Potassium channels
K+
Ca++Ca++
-cell
Insulin secretion
Potassium channels
K+
Ca++ Ca++-cell
Insulin secretion
farmaco
3. Durata del legame
GLIMEPIRIDEGLICLAZIDE MR
1. Biodisponibilità
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Glibenclamide: quali problemi nella pratica clinica?
- Emivita lunga - Crisi ipoglicemiche- Effetto sulla secrezione indipendente dai valori glicemici- Rischi cardiovascolari
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Glibenclamide: quali problemi nella pratica clinica?
- Emivita lunga - Crisi ipoglicemiche- Effetto sulla secrezione indipendente dai valori glicemici- Rischi cardiovascolari
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SUR-1 KIR6.2
SUR-1 SUR-1
SUR-1
SUR-1
KIR6.2 KIR6.2
KIR6.2
KIR6.2
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Pancreatic -cells / SUR1
Cardiac muscle / SUR2A
Vascular smooth muscle/ SUR2B
Physiologicalstimulus
Hyperglycemia Close channelsin T2D
Open channelsin IHD
Open channelsin IHDneurotransmitters
TherapeuticgoalTissue/receptors
Response
Muscle relaxation
Vasodilatation
Insulin secretion
Shorten action potential
Cardiac workHypoxia
Hypoxia
KKATPATP channel roles and distribution channel roles and distribution
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Glicemia delle 24 h nel soggetto sano e nel paziente diabetico
500
400
300
200
100
0800 1000 1200 1400 1600 1800 2000 2200 0000 0200 0400 0600 0800
Diabete tipo 2 scompensato
Gli
cem
ia (
mg
/dl)
Tempo (ore)
Pasto
FG
PPG
Pasto PastoNon-diabetico
SULFONILUREEassicurano un effetto prolungato (monosomministrazione)minore rischio di ipoglicemieminori rischi cardiovascolari
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-10 - 6 - 2 0 + 2 + 6 +10 +14
100
75
50
25
0
Fu
nzi
on
e b
eta
cellu
lare
Stadi del Diabete di tipo 2 in rapporto allafunzione beta cellulare
Lebovitz, 2000
IGT Iperglicemiapostprandiale
DMT2
Fase 1
DMT2
Fase 2 DMT2Fase 3
monoterapia
terapia combinata
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• Vecchi e Nuovi farmaci
• Sono tutti uguali?
• Vantaggi / Svantaggi
• Quali/Quando
Ipoglicemizzanti orali cheIpoglicemizzanti orali chestimolano la secrezione insulinicastimolano la secrezione insulinica
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Struttura dei secretagoghi
Repaglinide
Meglitinide
Glibenclamide(Glyburide)
H2N
HO O
HO O
HN
O
OH
O O
HN
N
HN
O
OHO
HN
O
S
O
O
O
HN
HNO
CI
Nateglinide
D-phenylalanineMitiglinide
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Cinetica della attivazione (T1/2-on) e della disattivazione (T1/2-off) dei canali del K ATP-dipendenti
T 1
/2
(min
ute
s)
0
40
80
120
160
200
Nateglinide Repaglinide Glyburide Glimepiride
T1/2-on
T1/2-off
Weaver ML et al. Drug Metab Dispos 2001;29:415–21