Η ΘΕΣΗ ΤΗΣ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗΣ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΟΥ ΔΙΑΒΗΤΗ ΤΥΠΟΥ 2 Ευάγγελος Λυμπερόπουλος Λέκτορας Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων

ΑΝΤΙΔΙΑΒΗΤΙΚΗ ΑΓΩΓΗ

Ελάττωση Κινδύνου με 1% Ελάττωση της HbA1c UKPDS 35: Σημαντική Ελάττωση του Κινδύνου των Επιπλοκών του T2DM με κάθε Ελάττωση κατά 1% στη μέση HbA1c N=3642 Ελάττωση Κινδύνου με 1% Ελάττωση της HbA1c P <0,0001 P=0,035 P=0,021 P <0,0001 P <0,0001 15 30 45 14% 12% 16% 19% 21% 37% 43% UKPDS 35*: Σημαντική Ελάττωση του Κινδύνου για τις Επιπλοκές του T2DM με κάθε Ελάττωση κατά 1% στη μέση HbA1c† Όπως σημειώθηκε νωρίτερα, τα δεδομένα από την Προοπτική Μελέτη για το Διαβήτη στο ΗΒ (UK Prospective Diabetes Study) (UKPDS) 35 απέδειξαν ότι κάθε ελάττωση κατά 1% στην ενημερωμένη HbA1c (δηλ, μετρούμενη με την πάροδο του χρόνου ως ενημερωμένη μέση τιμή των ετήσιων μετρήσεων) ελάττωσε των κίνδυνο των μικροαγγειακών επιπλοκών κατά 37%.1 1% ελάττωση στα επίπεδα της HbA1c βρέθηκε επίσης ότι ελαττώνει τον κίνδυνο της περιφερειακής αγγειακής νόσου κατά 43%, του εμφράγματος του μυοκαρδίου κατά 14%, του αγγειακού εγκεφαλικού επεισοδίου κατά 12%, της συμφορητικής καρδιακής ανεπάρκειας κατά 19%, και τη θνητότητα που σχετίζεται με το διαβήτη κατά 21%. Δεν υπήρχε ένδειξη ενός ουδού της HbA1c για τις επιπλοκές πάνω από τον οποίο δεν αύξανε περαιτέρω ο κίνδυνος ή κάτω από τον οποίο δεν ελαττωνόταν περαιτέρω. Για αυτό το λόγο δεν υποδείχθηκε κάποια επιδιωκόμενη τιμή για την HbA1c από τους ερευνητές της μελέτης. Ωστόσο, ο κίνδυνος φάνηκε να είναι μικρότερος στους ασθενείς με επίπεδα HbA1c <6,0%, και οποιαδήποτε ελάττωση των επιπέδων της HbA1c είναι πιθανό να μειώσει τον κίνδυνο σε ασθενείς με σακχαρώδη διαβήτη τύπου 2 (T2DM). *Προοπτική ανάλυση παρατήρησης των ασθενών της UKPDS (n=4585, ανάλυση επίπτωσης, n=3642, ανάλυση σχετικού κινδύνου), μέσος όρος 10,0 έτη παρακολούθησης †Υπολογιζόμενα πηλίκα κινδύνου (95% CI) μεταξύ της ενημερωμένης μέσης HbA1c και μικροαγγειακά καταληκτικά σημεία (αμφιβληστροειδοπάθεια, νεφροπάθεια, και νευροπάθεια), ακρωτηριασμός κάτω άκρων ή θανατηφόρος περιφερική αγγειακή νόσος, MI, αγγειακό εγκεφαλικό επεισόδιο, CHF, επέμβαση για καταρράκτη, και θάνατος που σχετίζεται με το διαβήτη. Τα δεδομένα τροποποιήθηκαν σύμφωνα με την ηλικία κατά τη διάγνωση του διαβήτη, το φύλο, την εθνική ομάδα, το κάπνισμα, την παρουσία πρωτεϊνουρίας, την SBP, την HDL-C, την LDL-C, και τα TG Βιβλιογραφία Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321: 405–412. Μικροαγγειακή νόσος PVD MI Αγγειακό εγκεφαλικό επεισόδιο CHF Επέμβαση για καταρράκτη Θάνατος που σχετίζεται με διαβήτη CHF=συμφορητική καρδιακή ανεπάρκεια, HbA1c=αιμοσφαιρίνη A1c, PVD=περιφερειακή αγγειοπάθεια, MI=έμφραγμα μυοκαρδίου Προσαρμογή από Stratton IM, et al. BMJ. 2000; 321: 405–412.

ΣΤΟΧΟΣ ΑΝΤΙΔΙΑΒΗΤΙΚΗΣ ΑΓΩΓΗΣ HbA1c<7% ADA Guidelines 2009

Μηχανισμός δράσης αντιδιαβητικών ουσιών Μεγλιτινίδες: Αύξηση της πρώιμης έκκρισης ινσουλίνης Στομάχι Αναστολείς α-γλυκοσιδασών Μείωση της απορρόφησης υδατανθράκων GLP-1 ανάλογα DPP4 αναστολεις Διέγερση της έκκρισης ινσουλίνης Καταστολη γλυκαγονης Έντερο Πάγκρεας Σουλφονυλουρίες: Διέγερση της έκκρισης ινσουλίνης Λιπώδης ιστός Ήπαρ Μύες Διγουανίδια: Μείωση της παραγωγής γλυκόζης από το ήπαρ Ελάττωση της αντίστασης στην ινσουλίνη - - + Γλιταζόνες (Θειαζολιδινεδιόνες): Μείωση της αντίστασης στην ινσουλίνη

ΠΩΣ ΔΡΟΥΝ ΟΙ ΓΛΙΠΤΙΝΕΣ??

Ανοχή Γλυκόζης από το στόμα και αντίστοιχης IV Έγχυσης 50 100 150 200 –30 30 60 90 120 180 210 Χρόνος (λεπτά) 400 50 g Γλυκόζη 300 Ινσουλίνη πλάσματος (pmol/L) Γλυκόζη πλάσματος (mg/dL) 200 100 Απόδειξη μιας Γαστρεντερικής «Επίδρασης των Ινκρετινών»: Διαφορετική Ανταπόκριση στη Γλυκόζη από το στόμα έναντι της IV Γλυκόζης Αυτή η διαφάνεια παρουσιάζει δεδομένα από την ίδια μελέτη απεικονίζοντας τα επίπεδα της γλυκόζης και της ινσουλίνης σε ανταπόκριση μιας ισογλυκαιμικής ενδοφλέβιας (IV) έγχυσης γλυκόζης (σχεδιασμένη να μιμηθεί το προφίλ του πλάσματος που επιτυγχάνεται με τη φόρτιση με γλυκόζη από το στόμα) σε αντιπαράθεση με τα επίπεδα που ακολουθούν φόρτιση 50 g γλυκόζης από το στόμα.1 Η αριστερή γραφική παράσταση απεικονίζει τα επίπεδα γλυκόζης στο πλάσμα σε ανταπόκριση σε φόρτιση με γλυκόζη από το στόμα σε σύγκριση με αντίστοιχη IV έγχυση γλυκόζης, αποδεικνύοντας βασικά παρόμοια αύξηση και ελάττωση των επιπέδων γλυκόζης πλάσματος. Ωστόσο, η εκκριτική ανταπόκριση της ινσουλίνης (β-κύτταρα) ήταν δραματικά διαφορετική, όπως φαίνεται στη δεξιά γραφική παράσταση. Ενώ η φόρτιση από το στόμα συνοδεύτηκε από μια μεγάλη αύξηση των επιπέδων ινσουλίνης στο πλάσμα, η έκκριση ινσουλίνης που έπεται της ισογλυκαιμικής IV έγχυσης γλυκόζης ήταν δραματικά χαμηλότερη. Αυτή η διαφορά αποδίδεται στη δραστηριότητα των ινκρετινών, οι οποίες εκκρίνονται ως ανταπόκριση στην παρουσία τροφής στο γαστρεντερικό σωλήνα και όχι όταν η γλυκόζη χορηγείται παρεντερικά. Επομένως η επίδραση των ινκρετινών συνίσταται σε διαφορετική έκταση έκκρισης ινσουλίνης που παρατηρείται μετά από πέψη της γλυκόζης σε σύγκριση με αυτή που παρατηρείται μετά από μια ισογλυκαιμική IV έγχυση (δηλ. η σκιασμένη περιοχή στη δεξιά γραφική παράσταση). Αυτά τα δεδομένα υποδηλώνουν ότι οι ινκρετίνες και όχι απλώς οι άμεσες δράσεις της γλυκόζης, επηρεάζουν της εκκριτική ανταπόκριση της ινσουλίνης. Βιβλιογραφία Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986; 63: 492–498. –30 30 60 90 120 150 180 210 Χρόνος (λεπτά) Από το στόμα IV N=6 IV=ενδοφλέβια Προσαρμογή από Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.

Οι Ινκρετίνες GLP-1: Πεπτίδιο που ομοιάζει στη γλυκαγόνη -1 A G F S V H E A T T D S Y E Q A K K L A F R V W I E G G GIP: Εξαρτώμενο από τη γλυκόζη ινσουλινοτρόπο πεπτίδιο Το GLP-1 και το GIP είναι Ινκρετίνες που εμπλέκονται στην Ομοιόσταση της Γλυκόζης Το πεπτίδιο που ομοιάζει στη γλυκαγόνη-1 (GLP-1) και το εξαρτώμενο από τη γλυκόζη ινσουλινοτρόπο πεπτίδιο (GIP) είναι πολυπεπτίδια που προέρχονται από το έντερο και ανήκουν στην οικογένεια των ινκρετινών.1 Το GLP-1, ένα πεπτίδιο 30/31 αμινοξέων, είναι προϊόν του ίδιου γονιδίου που κωδικοποιεί τη γλυκαγόνη και διαχωρίζεται, όπως η γλυκαγόνη, από το προϊόν της μετάφρασης του γονιδίου, την προγλυκαγόνη. Το GIP, ένα πεπτίδιο 42 αμινοξέων, ανήκει στην ίδια οικογένεια πρωτεϊνών και διαχωρίζεται από ένα πρόγονο 153 αμινοξέων.1 Η πάνω εικόνα απεικονίζει την αλληλουχία των αμινοξέων του GLP-1. Δημιουργείται μια δομή τυχαίας σπείρας από τα πρώτα επτά κατάλοιπα αμινοξέων, που ακολουθείται από μια ελικοειδή περιοχή (7–14), μια συνδετική περιοχή (15–17), και μια ακόμη ελικοειδή περιοχή (18–29). Η Ν-τελική περιοχή τυχαίας σπείρας αλληλεπιδρά με το κύριο τμήμα πρόσδεσης του υποδοχέα του GLP-1. Η κάτω εικόνα απεικονίζει την αλληλουχία των αμινοξέων του GIP. Η Ν-τελική περιοχή είναι παρόμοια με αυτή του GLP-1 και προσδένεται στον υποδοχέα του GIP στα παγκρεατικά β-κύτταρα.1 Η ελικοειδής περιοχή είναι συνεχής—χωρίς συνδετική περιοχή—και εκτείνεται από το κατάλοιπο 6 έως το 28.2 Βιβλιογραφία Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia. 2004; 47: 357–366. Alaña I, et al. NMR structure of the glucose-dependent insulinotropic polypeptide fragment, GIP(1–30)amide. Biochem Biophys Res Comm. 2004; 325: 281–286. A G F S Y I M K H Y E T I D S A D I Q N Q D K G A F N K L K V W Q L W D K T N I Q H Τα αμινοξέα που απεικονίζονται με χρυσό είναι ομόλογα στη δομή με τη γλυκαγόνη.

GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake L-cell (ileum) ProGIP Proglucagon GLP-1 [7–37] GIP [1–42] GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake This schematic compares the synthesis and secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both GLP-1 and GIP are released from the gut in response to nutrient intake: primarily glucose and fat.1 GLP-1 is synthesized from proglucagon in specialized endocrine L-cells located in the distal intestinal mucosa. GIP is synthesized in K-cells located in the proximal intestinal mucosa. Reference Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003; 26: 2929–2940. K-cell (jejunum) GLP-1 [7–36 NH2] GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1 Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.

Iνκρετίνες: Ρύθμιση και Δράσεις Πρόσληψη γεύματος Inactive GLP-1 and GIP Ανενεργές μορφές GLP-1 GIP DPP-IV Διέγερση Ορμονών (Ινκρετινών) από το ΓΕΣ (Eνεργές): GLP-1 GIP GLP-1 GIP GLP-1 και GIP Aυξημένη Έκκριση Ινσουλίνης από τα β-κύτταρα-γλυκοζο-εξαρτώμενη  Γλυκόζης Αίματος GLP-1 GLP-1 Μείωση τηςΈκκρισης Γλυκαγόνης από τα α-κύτταρα-γλυκοζο-εξαρτώμενη GLP-1: Glucagon Like Peptide 1 GIP: Glucagon Insulinotropic Polypeptide DPP-4: DiPeptidyl - Peptidase

GLP-1 Δράσεις στο άνθρωπο ↓ Υπερλειτουργία β - κυττάρου Εγκεφαλος Προκαλεί κορεσμό και μειώνει την όρεξη DISCUSSION By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion. BACKGROUND GLP-1 is secreted from L cells of the small intestine. GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169. Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520. α-κύτταρα: μείωση μεταγευματικής έκκρισης γλυκαγόνης ↑Απόκριση β - κυττάρου Ήπαρ: μείωση γλυκαγόνης μειώνει την ηπατική έξοδο γλυκόζης β-κύτταρα: Αυξάνει τη γλυκοζοεξαρτώμενη έκκριση ινσουλίνης Στόμαχος: Ρυθμίζει την κένωση του στομάχου Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

Το ενδογενές GLP-1 αποδομείται ταχέως από την DPP-IV Ανθρώπειος ειλεός, GLP-1 παράγοντα L-κύτταρα Τριχοειδή, Δι-Πεπτιδυλ- Πεπτιδάση-IV (DPP-IV) Native GLP-1 is rapidly degraded by DPP-IV GLP-1 is stored in intestinal L-cells. As active GLP-1 is secreted from these cells, it is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV) resulting in the inactive, N-terminally truncated form, GLP-1-(9-36)amide. More than 50% of plasma GLP-1 appears to be in this inactive form. In this slide, immunohistochemical staining shows the very close proximity of active GLP-1 in the L-cells and DPP-IV in the capillaries within the human ileum. References Hansen et al. Endocrinology 1999;140:5356–5363 Διπλή ανοσο-ιστοχημική χρώση για την DPP-IV (ερυθρό) και το GLP-1 (πράσινο) σε ανθρώπειο ειλεό Προσαρμογή από: Hansen et al. Endocrinology 1999;140:5356–5363.

Παθοφυσιολογία του ΣΔΤ2: Πολυπαραγοντική και Πολυορμονική διαταραχή Αντίσταση στην ινσουλίνη Διαταραχή έκκρισης ινσουλίνης Υπεργλυκαιμία Yπεργλυκαγοναιμία Μειωμένη ινκρετινική δράση Over the last decade, we have embraced an understanding that treating type 2 diabetes effectively -- even preventing type 2 diabetes, and treating it at its earliest stages -- requires a focus on a number of core defects. Prior to the introduction of pharmacologic agents that could provide an incretin effect, we focused on 2 issues: treating insulin resistance, which we can now do more effectively than ever before; and, doing things to modulate the effects of insulin deficiency, whether relative or absolute. Virtually all of our therapies are directed at 1 of these 2 core defects.

Στρατηγικές Ενίσχυσης της Δράσης Ινκρετίνης στον Διαβήτη A] Ανάλογα του Glucagon-like peptide-1 * Liraglutide Αγωνιστές υποδοχέων GLP-1* Εξενατίδη (Exenatide) B] Αναστολείς της Διπεπτυλ πεπτιδάσης – IV (DPP-IV)** Vildagliptin Sitagliptin Saxagliptin * Ινκρετινο - μιμητικές ουσίες ** Γλιπτίνες

Αναστολείς DPP- 4 Galvus® Januvia® A. MK-0431 (Sitagliptin), Merck, Sharp & Dohme B. NVP-LAF 237 (Vildagliptin), Novartis Galvus® Januvia® C. BMS-47718 (Saxagliptin), Bristol-Myers Squibb D. Aminomethylpyridine, Roche Demuth et al. 2005; Biochim Biophys Acta 1751: 33-44

Θεραπείες σε ανάπτυξη Αναστολείς DPP- 4: Σκεπτικό Ref 1, p 87, ¶1, L1-9,11-13 Ref 2, p 370, C1, ¶1, L6-9 Μικτό γεύμα Έκκριση εντερικού GLP-1 Ενεργό GLP-1 (7-36) Both GLP-1 and glucose-dependent insulinotropic peptide (GIP) are incretins; i.e., gut peptides that are released from the GI tract in response to a meal to potentiate glucose-dependent insulin release.1 The physiologic role of incretin hormones in maintaining glycemic control suggests that the incretin axis is a potential target for therapeutic intervention in type 2 diabetes.1 After their release into the circulation, both GLP and GIP are degraded by the enzyme dipeptidyl peptidase IV (DPP-IV).2 Prevention of the degradation of GLP-1 and GIP to their inactive metabolites via DPP-IV inhibition therefore may represent a rational approach to the treatment of type 2 diabetes.1 Ref 1, p 87, ¶1, L1-4 ¶1, L7-9 Ref 2, p 370, C1, ¶1, L6-9 p 94, C1, 21, L1-8 DPP-4 Ανενεργό GLP-1 (9-36) Αναστολέας DPP-4 DPP-IV=διπεπτιδυλική πεπτιδάση 4(IV) Προσαρμογή από Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372. References Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Invest Drugs 2003;12(1):87–100. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372.

Vildagliptin: Ένας Ισχυρός και Εκλεκτικός Αναστολέας της DPP-4 O H Αναστολέας της DPP-4 με υψηλή εκλεκτικότητα Εμφανίζει υψηλή συγγένεια για το ένζυμο στους ανθρώπους Αντιστρεπτή αναστολή Vildagliptin – ένας ισχυρός και εκλεκτικός αναστολέας της DPP-4 Η vildagliptin, προηγουμένως γνωστή ως LAF237, είναι ένας ισχυρός και αναστρέψιμος αναστολέας της διπεπτιδυλικής πεπτιδάσης-4 (DPP-4) του ανθρώπου με IC50 περίπου 3 nM. Η vildagliptin εμφανίζει υψηλή εκλεκτικότητα για τη DPP-4 και αργή κινητική πρόσδεσης με πολύ αργή ταχύτητα αποσύνδεσης: το σύμπλεγμα vildagliptin/DPP-4 αποσυνδέεται με χρόνο ημίσειας ζωής περίπου 55 λεπτών.1 Βιβλιογραφία Burkey BF, et al. Vildagliptin displays slow-tight binding to dipeptidyl peptidase (DPP)-4, but not DPP-8 or DPP-9. Poster 0788 presented at EASD 2006. Ακτινολογική κρυσταλλογραφική δομή της vildagliptin (πράσινο) προσδεδεμένη στην ενεργό θέση (κίτρινο) της DPP-4 στον άνθρωπο DPP-4=διπεπτιδυλική πεπτιδάση-4

Vildagliptin Enhances GLP-1 Levels in Patients with T2DM Meal Vildagliptin 100 mg (n=16) Placebo (n=16) 16.0 * * * 12.0 * * * * * Active GLP-1 (pmol/L) 8.0 * * * * * Vildagliptin Enhances GLP-1 Levels in Patients with T2DM In this randomized, double-blind study, patients with type 2 diabetes mellitus (n=16) received, on different days, a single dose of vildagliptin 100 mg or placebo, followed 30 minutes later by a standard evening meal containing radio-labeled glucose (75 g), allowing a meal tolerance test (MTT) to be carried out.1 Plasma samples during the MTT were taken and glucagon-like peptide-1 (GLP-1) levels estimated by enzyme-linked immunosorbent radioimmune assay using an N-terminal-specific antibody. Following dosing with vildagliptin 100 mg, there was a prompt and virtually complete suppression of plasma dipeptidyl peptidase-4 (DPP-4) activity.1 DPP-4 inhibition was associated with a significant post-meal increase in GLP-1 (and glucose-dependent insulinotropic peptide; data not shown), which persisted for 14 hours covering the whole overnight fasting period until the next morning.1 This study demonstrated that treatment with vildagliptin leads to increased GLP-1 levels that persist well beyond the post-meal period. Reference 1. Balas B, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007; 92: 1249–1255. 4.0 0.0 17:00 20:00 23:00 02:00 05:00 08:00 GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus *P <0.05. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Time

OGTT 30 λεπτά μετά την εφάπαξ δόση Vildagliptin από το στόμα (100 mg) 120 Εικονικό φάρμακο (n=16) Vildagliptin 100 mg (n=15) 100 Ινσουλίνη (pmol/L) 80 Δόση 60 40 20 −90 −60 −30 30 60 90 120 150 180 210 240 270 300 22.5 Γλυκόζη (mmol/L) 17.5 12.5 Η Vildagliptin ενισχύει τη Λειτουργία των Νησιδιακών Κυττάρων αυξάνοντας την Έκκριση Ινσουλίνης και ελαττώνοντας την Έκκριση Γλυκαγόνης Οι σχέσεις της ανταπόκρισης σε εφάπαξ δόσεις vildagliptin από το στόμα αξιολογήθηκαν σε αυτή την τυχαιοποιημένη, ανοικτή, ελεγχόμενη με εικονικό φάρμακο διασταυρούμενη μελέτη 16 ασθενών με σακχαρώδη διαβήτη τύπου 2 χρησιμοποιώντας την δοκιμασία ανοχής γλυκόζης από το στόμα.1 Εφάπαξ δόσεις από το στόμα εικονικού φαρμάκου ή vildagliptin χορηγήθηκαν μετά από ολονύκτια νηστεία ακολουθούμενες 30 λεπτά αργότερα από φόρτιση με 75 g γλυκόζης από το στόμα. Αξιολογήθηκαν τα επίπεδα ινσουλίνης πλάσματος (κορυφή), της γλυκόζης (μέσο) και της γλυκαγόνης (κάτω).1 Η εφάπαξ δόση vildagliptin 100 mg αύξησε σημαντικά την περιοχή κάτω από την καμπύλη (AUC) για την ινσουλίνη και ελάττωσε σημαντικά τις AUC για τη γλυκόζη και τη γλυκαγόνη. Αυτή η μελέτη αποδεικνύει ότι η vildagliptin ενισχύει τη λειτουργία των νησιδιακών κυττάρων αυξάνοντας την έκκριση ινσουλίνης και ελαττώνοντας την έκκριση γλυκαγόνης μειώνοντας με αυτό τον τρόπο τα επίπεδα γλυκόζης. Βιβλιογραφία He YL, et al. Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. J Clin Pharmacol 2007; 47: 633-641. 7.5 −90 −60 −30 30 60 90 120 150 180 210 240 270 300 140 Γλυκαγόνη (ng/L) 120 100 80 60 −90 −60 −30 30 60 90 120 150 180 210 240 270 300 OGTT=δοκιμασία ανοχής γλυκόζης από το στόμα *P <0,01. He YL, et al. J Clin Pharmacol 2007; 47: 633-641. Χρόνος

Vildagliptin Enhances α-cell Sensitivity to Glucose Placebo 24 24 Vilda wk 0 (50 mg twice daily, n=14) PBO wk 0 (n=14) PBO wk 12 (n=14) Vilda wk 12 (50 mg twice daily, n=14) 22 22 20 20 Glucagon (pmol/L) Glucagon (pmol/L) 18 18 16 16 Vildagliptin Enhances α-cell Sensitivity to Glucose This was a 12-week, double-blind, placebo-controlled, randomized, parallel-group study in patients with type 2 diabetes mellitus. One of the study’s objectives was to determine the effects of vildagliptin 50 mg twice daily on glucagon secretion.1 In this study, islet function was analyzed by intravenous glucose infusion (25 mM glucose ramp) after a 10-hour fast. The test was performed before (Week 0) and after (Week 12) treatment in patients randomized to receive vildagliptin 50 mg twice daily or placebo. Treatment with vildagliptin enhanced the ability of the α-cell to sense glucose, producing a significant decrease in plasma glucagon levels during the glucose ramp test compared with baseline (Week 0). In contrast, placebo had little effect on plasma glucagon levels. These data indicate that 12 weeks of treatment with vildagliptin 50 mg twice daily increases α-cell sensitivity and responsiveness to glucose. Reference 1. Data on file, Novartis Pharmaceuticals, LAF237A2344. * 14 * 14 * * 12 12 4.0 8.0 12.0 16.0 20.0 24.0 28.0 4.0 8.0 12.0 16.0 20.0 24.0 28.0 Glucose (mmol/L) Glucose (mmol/L) PBO=placebo; wk=week; vilda=vildagliptin *P <0.05 vs wk 0. Data on file, Novartis Pharmaceuticals, LAF237A2344.

Vildagliptin Suppresses Glucagon Secretion Meal 20 PBO (n=16) 10 Vilda 100 mg (n=16) −10 Delta glucagon (ng/L) −20 * −30 * Vildagliptin Suppresses Glucagon Secretion In this randomized, double-blind study, patients with type 2 diabetes mellitus (n=16) received, on different days, a single dose of vildagliptin 100 mg or placebo, followed 30 minutes later by a standard evening meal containing radio-labeled glucose (75 g), allowing a meal tolerance test (MTT) to be carried out.1 Plasma samples during the MTT were taken and glucagon levels estimated by radioimmune assay. Administration of vildagliptin 100 mg was associated with a significantly greater suppression of glucagon than placebo during MTT (P <0.02); these effects persisted throughout the overnight period.1 These results show that vildagliptin suppresses glucagon secretion throughout the overnight period. Reference 1. Balas B, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab 2007; 92: 1249-1255. −40 * * −50 * * * * * −60 17:00 20:00 23:00 02:00 05:00 08:00 Time PBO=placebo; vilda=vildagliptin. *P <0.05 vs PBO. Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255.

Incretin response diminished Incretin activity prolonged Blocking DPP-4 Can Improve Incretin Activity and Correct the Insulin:Glucagon Ratio in T2DM  Insulin  Glucagon Hyperglycemia Incretin response diminished Further impaired islet function T2DM  Insulin  Glucagon Improved glycemic control Incretin activity prolonged Improved islet function DPP-4 inhibitor Blocking DPP-4 Can Improve Incretin Activity and Correct the Insulin:Glucagon Ratio in T2DM Patients with type 2 diabetes mellitus (T2DM) have an imbalance in their insulin:glucagon ratio, which is largely responsible for hyperglycemia.1 By inhibiting dipeptidyl peptidase-4 (DPP-4) and prolonging incretin activity, this imbalance can be corrected and glycemic control improved, as shown by the schematic on this slide.2 Pancreatic islet dysfunction is considered a prerequisite for T2DM. The activity of both β-cells and -cells is impaired such that insulin secretion is decreased and glucagon secretion is increased. In addition, patients with diabetes have reduced concentrations of circulating incretins. This impairment exacerbates the defects in insulin and glucagon secretion because incretins act to stimulate glucose-sensitive insulin response and suppress glucagon release.1,2 By inhibiting DPP-4, incretin activity can be prolonged, leading to increased levels of active incretins. As a result, glucose-sensitive insulin and glucagon responses are corrected, and glycemic control is improved.2 References Unger RH. Alpha- and beta-cell interrelationships in health and disease. Metabolism. 1974; 23: 581–593. Ahrén B. Inhibition of dipeptidyl peptidase-4 (DPP-4)—a novel approach to treat type 2 diabetes. Curr Enzyme Inhib. 2005; 1: 65–73. DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.

Vildagliptin: Βελτιώνει τη Μάζα των β-κυττάρων (Μοντέλο Παγκρεατικής Αύξησης σε Νεογέννητους Αρουραίους) Ινσουλίνη Vildagliptin 60 mg/kg 21 ημέρες Φορέας Αντιγραφή Απόπτωση Μάζα -κυττάρων Φορέας Vilda P <0,05 0,00 0,02 0,04 0,06 0,08 0,10 0,12 0,14 120 P <0,001 2,5 100 2,0 Μάζα -κυττάρων (mg) BrdU-Θετικά κύτταρα (%) 80 Vildagliptin: Βελτιώνει τη Μάζα των β-κυττάρων (Μοντέλο Παγκρεατικής Αύξησης σε Νεογέννητους Αρουραίους) Στο σακχαρώδη διαβήτη τύπου 2 (T2DM) παρατηρείται προοδευτική διαταραχή της λειτουργίας των β-κυττάρων και απώλεια της μάζας των β-κυττάρων κυρίως εξαιτίας της αυξημένης απόπτωσης. Επομένως, ένα επιθυμητό γνώρισμα ενός αντιδιαβητικού παράγοντα είναι η ικανότητα να βελτιώνει τη μάζα των β-κυττάρων. Σε αυτή τη μελέτη, αρουραίοι 48 ωρών ταξινομήθηκαν για να λάβουν φορέα ή vildagliptin (60 mg/kg, po) από την Ημέρα 2. Μετά από 7 ή 20 ημέρες στα ζώα ενέθηκε 5-βρωμο-2 δεοξυουριδίνη (BruD) και θυσιάστηκαν και στη συνέχεια συλλέχθηκε ο παγκρεατικός ιστός. Η παγκρεατική ινσουλίνη έγινε ορατή στα τεμάχια του ιστού με χρώση με ανοσοϋπεροξειδάση. Η αντιγραφή και η απόπτωση των β-κυττάρων έγινε ορατή με BrdU και ApopTag® χρώση, αντίστοιχα. Χρησιμοποιώντας μορφομετρική ανάλυση, η μάζα των β-κυττάρων εκτιμήθηκε διαιρώντας την περιοχή που ήταν θετική στην ινσουλίνη με τη συνολική παγκρεατική περιοχή για να προκύψει η περιοχή των β κυττάρων. Την Ημέρα 7, η αντιγραφή των β-κυττάρων αυξήθηκε κατά >8 φορές (P <0,001) και η απόπτωση ελαττώθηκε κατά 65% (P <0,05) στην ομάδα της vildagliptin σε σύγκριση με την ομάδα του φορέα. Υπήρχε μια τάση για αύξηση της μάζας β-κυττάρων. Την Ημέρα 21, ήταν εμφανής μια αύξηση κατά 75% στην επιφάνεια και τη μάζα των β-κυττάρων και αυτό ήταν στατιστικά σημαντικό (P <0,05). Η vildagliptin βελτιώνει τη μάζα των β-κυττάρων διεγείροντας την αντιγραφή και αναστέλλοντας την απόπτωση σε αυτό το μοντέλο ανακύκλωσης των β-κυττάρων σε αρουραίους. Ωστόσο, τα δεδομένα πρέπει να ερμηνευτούν με προσοχή εξαιτίας των διαφορών στη φυσιολογία της ανακύκλωσης των β-κυττάρων στους αρουραίους έναντι των ανθρώπων. Βιβλιογραφία 1. Duttaroy A, et al. The DPP-4 inhibitor vildagliptin increases pancreatic beta cell neogenesis and decreases apoptosis. Poster 572 presented at ADA 2005. ApopTag-Θετικά κύτταρα (%) 1,5 P <0,05 60 1,0 40 20 0,5 0,0 Φορέας Vilda Φορέας Vilda Ημέρα 7 Ημέρα 21 Vilda=vildagliptin Duttaroy A, et al. Diabetes. 2005; 54 (suppl 1): A141. Abstract 572-P and poster presented at ADA.

Durability of β-cell Function over 2 Years Treatment period Wk 0–52 Washout Treatment period Wk 56–108 Washout 50 45 Mean ISR/G (pmol/min/m2/mM) 40 35 Durability of β-cell Function over 2 Years In type 2 diabetes mellitus (T2DM) there is a progressive impairment of pancreatic β-cell function and loss of β-cell mass, largely due to increased apoptosis. Therefore, a desirable attribute for an anti-diabetic agent is an ability to improve β-cell function. In this randomized, double-blind, placebo-controlled trial comprising a 52-week core study with a 4-week washout period followed by a 52-week extension study followed by a further 4-week washout, drug-naïve patients with T2DM and mild hyperglycemia (HbA1c 6.2–7.2%) were randomized to receive vildagliptin 50 mg once daily (n=63 at Week 0, 49 at Week 108, 46 at Week 112) or placebo (n=62 at Week 0, 40 at Week 108, 41 at Week 112). Insulin-secretory rate relative to glucose concentration (ISR/G, β-cell function) tended to be greater after 2 years than after 1 year of vildagliptin treatment, and was considerably lower in those patients who received placebo. Mean ISR/[G] improved with vildagliptin treatment during both study periods, and returned to baseline during the washout periods. However the decrease of mean ISR/[G] observed during the second washout period following vildagliptin treatment was not as great as that observed during the first washout period, suggesting that some of the beneficial effects of vildagliptin treatment on β-cell function were maintained after the washout following 2-year treatment. In patients with mild hyperglycemia, vildagliptin appeared to attenuate the progressive deterioration in β-cell function and glycemic control seen in patients receiving placebo. Reference Scherbaum W, et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab. 2008; Epub ahead of print. 30 −8 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks) Placebo (n=40) Vildagliptin 50 mg once daily (n=49) ISR/G=insulin-secretory rate relative to glucose concentration Scherbaum WA, et al. Diabetes Obes Metab. 2008; Epub ahead of print.. 24

Vildagliptin Suppresses Endogenous Glucose Production Time Meal 17:00 20:00 23:00 02:00 05:00 08:00 * −0.3 −0.6 Delta EGP (mg/kg/min) −0.9 Vildagliptin Suppresses Endogenous Glucose Production In this randomized, double-blind study, patients with type 2 diabetes mellitus (n=16) received, on different days, a single dose of vildagliptin 100 mg or placebo, followed 30 minutes later by a standard evening meal containing radio-labeled glucose (75 g), allowing a meal tolerance test (MTT) to be carried out.1 Plasma samples during the MTT were taken and endogenous glucose production (EGP) was assessed. This primarily reflects activity in the liver, with a small contribution from the kidney. In both the vildagliptin and placebo groups, there was a prompt suppression of EGP following the meal. However, within 60 minutes of ingestion of the meal, suppression of EGP was greater with vildagliptin, as it was at all subsequent time points. At 0–240, 0–480, and 0–840 minutes after dosing, the suppression of EGP was 25%, 34%, and 59% greater (all P ≤0.01) with vildagliptin compared with placebo. The decrease in overnight EGP after vildagliptin correlated with the decrease in plasma glucagon (r= −0.49, P <0.05) and fasting plasma glucose concentration (r=0.55, P <0.03). The reduction in EGP is presumably a result of the observed increase in insulin to glucagon ratio. This study demonstrates that vildagliptin suppresses EGP, which persists throughout the overnight fast. Reference Balas, B et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab 2007; 92: 1249-1255. PBO (n=16) −1.2 Vilda 100 mg (n=16) −1.5 EGP=endogenous glucose production; PBO=placebo; vilda=vildagliptin *P <0.05 vs PBO. Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255.

Η Vildagliptin αυξάνει την ιστική ινσουλινοευαισθησία Duration: 6 weeks Vilda vs PBO Hyperinsulinemic Euglycemic Clamp * Insulin infusion 80 mU/m2•min Mean Rd difference=0.7 mg/kg•min 6.1 5.4 Glucose Rd (mg/kg•min) Vilda 50 mg twice daily (n=16) PBO (n=16) Vildagliptin Enhances Insulin Sensitivity This was a double-blind, placebo-controlled, randomized, cross-over study to determine the mechanism of action of vildagliptin on islet function and glucose utilization. Patients with type 2 diabetes mellitus received vildagliptin 50 mg twice daily or placebo for 6 weeks and then crossed over to the other treatment for 6 weeks. The study used a stepped hyperinsulinemic clamp technique to measure glucose utilization (the glucose rate of disappearance, a measure of insulin sensitivity) at insulin infusion of 20 mU/m2.min (LO) and 80 mU/m2.min (HI). During HI insulin infusion (80 mU/m2.min) vildagliptin significantly increased systemic glucose utilization compared with placebo (6.1 vs 5.4 mg/kg•min; P <0.05). These data indicate that vildagliptin 50 mg twice daily enhances insulin sensitivity to glucose by improving insulin-stimulated glucose utilization. Reference 1. Azuma K, et al. Measurements of islet function and glucose metabolism with the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab 2007; [Epub] PBO=placebo; Rd=rate of disappearance; vilda=vildagliptin *P <0.05. Azuma K, et al. J Clin Endocrinol Metab 2007; [Epub].

ΦΑΡΜΑΚΟΚΙΝΗΤΙΚΕΣ ΙΔΙΟΤΗΤΕΣ ΤΗΣ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗΣ Βιοδιαθεσιμότητα: >80% Σύνδεση με πρωτεΐνες: Πολύ μικρή Μεταβολισμός: Δεν παρεμβαίνει στο Ρ450 Απέκκριση: Κατά 85% στα ούρα + κατά 15% στα κόπρανα Διάρκεια δράσης: Τουλάχιστον 12 ώρες

Vildagliptin: Pharmacokinetics Rapid absorption after oral administration Dose-dependent, highly selective & rapid DPP-4 inhibition Bioavailability > 80%, no food effect Very low protein binding Metabolism: Hydrolysis Major metabolite is pharmacologically inactive Does not inhibit/induce or utilize P450 CYP Excretion: 85% excreted into urine, 15% in the faeces No drug-drug interaction with commonly prescribed agents No anticipated dose adjustment for special populations (e.g. renal impairment, hepatic impairment, elderly, ethnic populations) Data on file, Novartis Pharmaceuticals

Η ΚΛΙΝΙΚΗ ΕΜΠΕΙΡΙΑ ΜΕ ΤΗ ΧΡΗΣΗ ΤΗΣ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗΣ

Patient Exposure in Vildagliptin Clinical Programa Over 22,000 patients overall treated in the clinical program1 >14,400 exposed to vildagliptin Over 19,800 patients treated in completed studies2 >13,000 exposed to vildagliptin in completed studies Patient exposure by treatment duration in completed studies 3700 patients exposed to vildagliptin >1 year 1800 patients exposed to vildagliptin >2 years Patient Exposure in Vildagliptin Clinical Program To date, >22,000 patients have participated in completed vildagliptin clinical studies. More than 14,400 patients have been exposed to vildagliptin, with 3700 patients exposed for at least 1 year and 1800 patients receiving vildagliptin >2 years. More than 19,800 patients have been treated in completed studies, including >13,000 patients who have been exposed to vildagliptin. Reference Data on file, Novartis Pharmaceuticals. Data current as of August 27, 2008. aData on file, Novartis Pharmaceuticals. Current as of August 27, 2008. 1All Phase I-IV studies; 2All completed Phase I-IV studies: 40 Phase II-IV trials and 49 ED (Phase I) trials. 30 30

ΠΟΣΟ ΜΕΙΩΝΕΙ ΤΗΝ HbA1c??

Vildagliptin Effective across Hyperglycemia Spectrum Overall BL HbA1c ≤8% 8< HbA1c ≤9% 9< HbA1c ≤10% HbA1c >10% n= 1569 543 490 362 174 BL= 8.7 7.6 8.5 9.5 10.6 * Change from BL in HbA1c (%) * * Vildagliptin: Effective across Hyperglycemia Spectrum Pooled Analysis in Monotherapy 50 mg Twice Daily Data from four trials were pooled to assess the effect of vildagliptin 50 mg twice daily on HbA1c. All trials were double-blind, randomized, multicenter, parallel-group studies. Three trials lasted for 24 weeks; the fourth trial lasted for 52 weeks. Changes from baseline in HbA1c at 24 weeks for five patient groups were analyzed: 1) the pooled population overall (n=1569) 2) patients with baseline HbA1c ≤8% (n=543) 3) patients with baseline HbA1c >8% to ≤9% (n=490) 4) patients with baseline HbA1c >9% to ≤10% (n=362) 5) patients with baseline HbA1c >10% (n=174) Significant changes from baseline of 1.0%, 0.6%, 0.9%, 1.6%, and 1.9% were obtained for the overall, HbA1c ≤8%, HbA1c >8% to ≤9%, HbA1c >9% to ≤10%, and HbA1c >10% patient populations, respectively. These data demonstrate that vildagliptin is an effective glucose-lowering agent, offering glycemic control across a wide spectrum of patients with hyperglycemia. Reference Summary of Clinical Efficacy, 13 September 2007. Tables 2-1.5d1, 2-1.5d3. Novartis Pharmaceuticals. * * Vilda 50 mg twice daily BL=baseline; HbA1c-hemoglobin A1c; vilda=vildagliptin *P <0.001 from BL. HbA1c change from baseline to Week 24 (end point) pooled monotherapy intention-to-treat / primary intention-to-treat population. Data on file, Novartis Pharmaceuticals.

Vildagliptin Effective across Age Age <65 years Age >65 years n= 1326 243 BL= 8.7 8.4 Change from BL in HbA1c (%) Vildagliptin: Effective across Age Data from four trials were pooled to assess the effect of vildagliptin 50 mg twice daily on HbA1c in elderly patients. All trials were double-blind, randomized, multicenter, parallel-group studies. Three trials lasted for 24 weeks; the fourth trial lasted for 52 weeks. Changes from baseline in HbA1c at 24 weeks were analyzed for two patient groups categorized according to age: 1) patients aged <65 years (n=1326) 2) patients aged 65 years (n=243) Vildagliptin treatment produced identical and significant changes from baseline in HbA1c of 1.1% for both groups (P <0.01). These data demonstrate that vildagliptin is an effective glucose-lowering agent, providing the same level of glycemic control in elderly patients as in younger patients. Reference Summary of Clinical Efficacy, 13 September 2007. Tables 2-1.2d1. Novartis Pharmaceuticals. * * BL=baseline; vilda=vildagliptin *P <0.001 from BL. HbA1c change from baseline to Week 24 (end point) pooled monotherapy intention-to-treat / primary intention-to-treat population. Data on file, Novartis Pharmaceuticals. Vilda 50 mg twice daily

Vildagliptin Effective across a Range of BMIs BMI <30 kg/m2 BMI >30 kg/m2 BMI <35 kg/m2 BMI >35 kg/m2 n= 819 748 1202 365 BL= 8.7 8.6 8.7 8.6 Change from BL in HbA1c (%) Vildagliptin: Effective across a Range of BMIs Pooled Analysis in Monotherapy 50 mg Twice Daily Data from four trials were pooled to assess the effect of vildagliptin 50 mg daily on HbA1c in obese and non-obese patients. All trials were double-blind, randomized, multicenter, parallel-group studies. Three trials lasted for 24 weeks; the fourth trial lasted for 52 weeks. Changes from baseline in HbA1c at 24 weeks for four patient groups categorized according to weight were analyzed: 1) patients with baseline body mass index (BMI) <30 kg/m2 (n=819) 2) patients with baseline BM) 30 kg/m2 (n=748) 3) patients with baseline BMI <35 kg/m2 (n=1202) 4) patients with baseline BMI 35 kg/m2 (n=365) Significant changes from baseline of 1.1%, 0.9%, 1.1%, and 1.0% were obtained for the BMI patient groups <30 kg/m2, 30 kg/m2, <35 kg/m2, and 35 kg/m2, respectively (P <0.01). These data demonstrate that vildagliptin is an effective glucose-lowering agent, providing glycemic control in both obese and non-obese patients. Reference Summary of Clinical Efficacy, 3 December 2007. Tables 2-1.4d1, 2-1.4d3. Novartis Pharmaceuticals. * * * * Vilda 50 mg twice daily BL=baseline, BMI=body mass index; vilda=vildagliptin *P <0.001 from BL. HbA1c change from baseline to Week 24 (end point) pooled monotherapy intention-to-treat / primary intention-to-treat population. Data on file, Novartis Pharmaceuticals.

Ι. ΩΣ ΜΟΝΟΘΕΡΑΠΕΙΑ

Vildagliptin Monotherapy: Reductions in HbA1c over 24 Weeks Duration: 24 weeks Vildagliptin 50 mg once daily (n=84) Vildagliptin 50 mg twice daily (n=79) Vildagliptin 100 mg once daily (n=89) Placebo (n=88) Mean HbA1c (%) * Vildagliptin Monotherapy: Reductions in HbA1c over 24 Weeks This 24-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted to assess the efficacy and tolerability of vildagliptin at three different dose regimens. Drug-naïve patients (n=354) with type 2 diabetes mellitus (HbA1c 7.5–10.0%) were randomized to receive one of three vildagliptin doses (50 mg once daily, 50 mg twice daily, or 100 mg once daily) or placebo. Mean baseline HbA1c was ~8.4%. At end point, the between-treatment differences (vildagliptin − placebo) in HbA1c were −0.5, −0.7, and −0.9% for vildagliptin 50 mg once daily, 50 mg twice daily, and 100 mg once daily, respectively. Overall, the percentage of patients who achieved the target level of HbA1c <7% was significantly greater in the vildagliptin 50 mg once-daily (25%), vildagliptin 50 mg twice-daily (30%), and vildagliptin 100 mg once-daily (39%) groups compared with the placebo group (14%; P ≤0.01). Reference Pi-Sunyer F, et al. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007; 76: 132–138. ** ** Time (Weeks) HbA1c=hemoglobin A1c Primary intention-to-treat population. *P=0.01; **P <0.001 vs placebo. Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138.

Vildagliptin Monotherapy: Early and Sustained Effect at 1 Year Duration: 52 weeks Vildagliptin vs metformin 10.0 Vildagliptin 50 mg twice daily (n=511) Metformin 1000 mg twice daily (n=248) 9.0 8.0 Mean HbA1c (%) −1.0% Not non-inferior* Vildagliptin Monotherapy: Early and Sustained Effect at 1 Year This multicenter, randomized, double-blind study compared vildagliptin with metformin in drug-naïve patients with type 2 diabetes mellitus. This comprised a core study period of 52 weeks1 followed by a 52-week extension study.2 A total of 780 patients (HbA1c 7.5−11%) were randomized to receive either vildagliptin 50 mg twice daily or metformin 1000 mg twice daily. The adjusted mean change from baseline to end point at 52 weeks was −1.0 ± 0.1% in patients receiving vildagliptin and −1.4 ± 0.1% in those receiving metformin (significant changes from baseline for both drugs; P <0.001). The predefined criteria for statistical non-inferiority were not met. This study has demonstrated that vildagliptin 50 mg twice daily produces early, clinically meaningful reductions in HbA1c that are sustained for at least 1 year of treatment. References Schweizer A, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med. 2007; 24: 955–961. Göke B, et al. Efficacy and Safety of Vildagliptin Monotherapy during 2-Year Treatment of Drug-naïve Patients with Type 2 Diabetes: Comparison with Metformin. Horm Metab Res. 2008; 40: 892–895. 7.0 −1.4% 6.0 −4 4 12 20 28 36 44 52 Time (Weeks) Intention-to-treat population. *Non-inferiority end point not met, confidence interval = 0.28–0.65 (non-inferiority margin is defined by confidence interval upper limit of 0.4%). Schweizer A, et al. Diabet Med. 2007; 24: 955–961.

Gastrointestinal AE Incidence (%) Vildagliptin vs Metformin Study at 2 Years: Superior GI tolerability of vildagliptin vs metformin Duration: 104 weeks (including 52-week extension to the 52-week core study) Vildagliptin vs metformin 25.0 45.6 Gastrointestinal AE Incidence (%) ** Mean HbA1c (%) 9.5 Metformin 1000 mg twice daily Vildagliptin 50 mg twice daily 9.0 8.5 8.0 Not NI* 7.5 Vildagliptin vs Metformin Study at 2 Years: Superior Tolerability of Vildagliptin vs Metformin due to Much Lower Incidence of GI Events This was a 52-week extension to a 52-week, multicenter, randomized, double-blind study comparing vildagliptin 50 mg twice daily with metformin 1000 mg twice daily in drug-naïve patients with type 2 diabetes mellitus.1,2 The primary efficacy variable was the change from core baseline in HbA1c (%) at the end of the extension study. Safety assessments included adverse events.2 Vildagliptin and metformin had comparable efficacy at 24 weeks, but the non-inferiority was not established at Week 521 and the difference between the two drugs persisted to 104 weeks.2 In addition, more patients were rescued due to inadequate glycemic control in the vildagliptin group than in metformin group between Weeks 52 and 104.2 The improved control with metformin was associated with significantly more gastrointestinal events than vildagliptin.2 Thus, vildagliptin was not as well sustained over 2 years from a high baseline relative to either a thiazolidinedione or metformin, but vildagliptin was better tolerated compared with metformin in terms of gastrointestinal events. References Schweizer A, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med. 2007; 24: 955–961. Göke B, et al. Efficacy and Safety of Vildagliptin Monotherapy during 2-Year Treatment of Drug-naïve Patients with Type 2 Diabetes: Comparison with Metformin. Horm Metab Res. 2008; 40: 892–895. 7.0 6.5 −2 4 8 12 16 24 32 40 52 64 76 88 104 Time (Weeks) AE=adverse event; HbA1c=hemoglobin A1c *Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Göke B, et al. Horm Metab Res. 2008; 40: 892–895.

In monotherapy, Vildagliptin as Effective as Rosiglitazone at 24 Weeks Duration: 24 weeks Vilda vs rosi Overall Mean BL ~8.7% HbA1c >9% Mean BL ~10% n= 459 238 166 88 Change from BL in HbA1c (%) Vildagliptin versus Rosiglitazone Study: Vildagliptin as Effective as Rosiglitazone at 24 Weeks This was a 24-week, double-blind, randomized, active-controlled, parallel-group, multicenter study to compare the efficacy and tolerability of vildagliptin (50 mg twice daily) and rosiglitazone (8 mg once daily) in drug-naïve patients.1 There were significant adjusted mean changes in HbA1c from baseline to Week 24 of −1.1% and −1.3% for vildagliptin and rosiglitazone, respectively (P <0.001 for both drugs). Non-inferiority of vildagliptin 50 mg twice daily to rosiglitazone 8 mg once daily was established. In patients with high baseline HbA1c (>9%), larger reductions of −1.8% in vildagliptin-treated patients (baseline 10.0%) and −1.9% in rosiglitazone-treated patients (baseline 9.9%) were observed. This study demonstrates that vildagliptin is as effective as rosiglitazone at 24 weeks in reducing blood glucose levels in drug-naïve patients. In patients with high baseline levels, more substantial but similar decreases in Hb1Ac were obtained for vildagliptin and rosiglitazone. Reference Rosenstock J, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. A 24-week, double-blind, randomized trial. Diabetes Care 2007; 30: 217-223. Non-inferior* Vilda 50 mg twice daily Rosi 8 mg once daily BL=baseline; rosi=rosiglitazone; vilda=vildagliptin Primary intention-to-treat population. *Confidence interval= −0.01, 0.39 (non-inferiority margin is defined by confidence interval upper limit 0.4%). Rosenstock J, et al. Diabetes Care 2007; 30: 217-223.

… with Weight Loss Relative to Rosiglitazone Duration: 24 weeks Vilda vs rosi Overall BMI >35 kg/m2 n= 459 238 132 76 BL (kg)= 91 93 111 112 2.8 kg difference Weight change from BL (kg) Weight Loss Relative to Rosiglitazone This was a 24-week, double-blind, randomized, active-controlled, parallel-group, multicenter study to compare the efficacy and tolerability of vildagliptin (50 mg twice daily) and rosiglitazone (8 mg once daily).1 The primary intention-to-treat population comprised 697 patients (vildagliptin n=459; rosiglitazone n=238). No change in body weight was observed after 24 weeks of treatment with vildagliptin. This contrasted with an increase of 1.6 kg in the rosiglitazone treatment group; the between-treatment group difference was 1.9 kg (P <0.001). In the severely obese population (≥35 kg/m2), a decrease in body weight was observed (−1.1 kg) with vildagliptin. At 24 weeks, the 2.8 kg difference in body weight between vildagliptin and rosiglitazone for the subgroup of severely obese patients was significantly in favor of vildagliptin (P <0.001). Weight gain is a common side effect of a thiazolidinedione (TZD). Vildagliptin has been shown to be as effective as a TZD but does not cause weight gain. Reference Rosenstock J, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. A 24-week, double-blind, randomized trial. Diabetes Care 2007; 30: 217-223. * * Vilda 50 mg twice daily Rosi 8 mg once daily BL=baseline; BMI=body mass index; rosi=rosiglitazone; vilda=vildagliptin *P <0.001 vs rosi. Primary intention-to-treat population. Rosenstock J, et al. Diabetes Care 2007; 20: 217-223.

Vildagliptin vs. Rosiglitazone: Benefit / Risk Balance Vildagliptin vs. rosiglitazone: 104 weeks * Mean HbA1c (%) 1 Edema incidence (%) 2 Mean body weight (kg) 1  – 4.7, P<0.001‡ 104 weeks Vildagliptin 50 mg twice daily Rosiglitazone 8 mg once daily Time (weeks) Data on file, Novartis Pharmaceuticals, LAF237A2327E * Head-to-head vildagliptin vs. rosiglitazone comparison: 80 weeks extension to 24 weeks core study; Extension ITT population; ‡ statistically significant larger increase in body weight from baseline to endpoint was seen in the rosiglitazone group than in the vildagliptin group, p < 0.001 1) vildagliptin N= 354; rosiglitazone N=179; Observations censored at rescue med; error bars represent standard error values; 2) pitting edema, peripheral edema, and other edema;

Vildagliptin Monotherapy: Low Incidence of Hypoglycemic Events Pooled analysis at 24 weeks Patients Vilda 50 mg once daily N=655 n (%) Vilda 50 mg twice daily N=2251 n (%) Met <1 mg twice daily N=252 n (%) Rosi 8 mg once daily N=267 n (%) Acar <100 mg thrice daily N=220 n (%) PBO N=586 n (%) With >1 hypoglycemic events 2 (0.3) 7 (0.3) 1 (0.4) 1 (0.2) Discontinued for hypoglycemic events With grade 2 hypoglycemic events Vildagliptin Monotherapy: Incidence of Hypoglycemic Events Data from dose-ranging studies of vildagliptin and comparative studies of vildagliptin and metformin, rosiglitazone, acarbose, or placebo have been analyzed to determine the incidence of hypoglycemia up to 24 weeks. From a total of 2906 patients who have received vildagliptin 50 mg once or twice daily, only 0.3% of patients have experienced hypoglycemic events. No patients discontinued treatment as a result of hypoglycemia and there were no grade 2 events. These data demonstrate that the incidence of hypoglycemia with vildagliptin treatment is generally low and non-severe among drug-naïve patients with type 2 diabetes. Reference Adapted from Summary of Clinical Safety, 14 July 2006. Table 4-27; p. 93. Novartis Pharmaceuticals. Hypoglycemic events are defined as: (a) symptoms patient is able to self-treat and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2). Acar=acarbose; met=metformin; PBO=placebo; rosi=rosiglitazone; vilda=vildagliptin Adapted from Summary of Clinical Safety, 5 December 2007. Table 4-1g. Novartis Pharmaceuticals.

ΙΙ. ΣΕ ΣΥΝΔΥΣΜΟ ΜΕ ΜΕΤΦΟΡΜΙΝΗ

Mean Difference vs PBO BL ~8.4% Vildagliptin Add-on to Metformin: Effective HbA1c Reduction at 24 Weeks Duration: 24 weeks Vilda add-on to met Add-on Treatment to Metformin (2.1 g Mean Daily) Mean Difference vs PBO BL ~8.4% Change in HbA1c (%) -0.7 Vildagliptin Add-on to Metformin: Effective HbA1c Reduction at 24 Weeks This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 Eligible patients had received metformin monotherapy treatment for at least 3 months and had been on a stable dose of metformin (≥1500 mg daily) for at least 4 weeks. Treatment with vildagliptin as an add-on to metformin led to a significant dose-related decrease in HbA1c compared with placebo plus metformin. The between-treatment difference (ie, vildagliptin – placebo) in adjusted mean change in HbA1c from baseline to end point was −0.7 ± 0.1% (P <0.001) with vildagliptin 50 mg once daily and −1.1 ± 0.1% (P <0.001) with vildagliptin 50 mg twice daily. These results demonstrate that vildagliptin produces clinically meaningful, dose-related decreases in HbA1c levels at 24 weeks as add-on therapy in patients with T2DM inadequately controlled by metformin. Reference Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007; 30: 890–895. * * BL=baseline; HbA1c=hemoglobin A1c; met=metformin; PBO=placebo; vilda=vildagliptin Primary intention-to-treat population. *P <0.001 difference vs PBO. Bosi E, et al. Diabetes Care. 2007; 30: 890–895. Vilda 50 mg twice daily + met (n=143) Vilda 50 mg once daily + met (n=143)

Vildagliptin Add-on to Metformin: Proportion of Patients Reaching Treatment Target Duration: 24 weeks Vilda add-on to met Add-on Treatment to Metformin (2.1 g Mean Daily) BL HbA1c <8.0% BL HbA1c >8.0% to <8.5% Vilda 50 mg once daily + met Vilda 50 mg twice daily + met PBO + met Responders (%) Vildagliptin Add-on to Metformin: Proportion of Patients Reaching Treatment Target This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 A patient was considered to have responded to treatment if their end-point HbA1c level was <7.0%. In patients with baseline HbA1c ≤7.9%, 50% and 54% of patients who received vildagliptin 50 mg once or twice daily, respectively, reached their treatment target compared with 14% of patients receiving placebo. In patients with intermediate baseline HbA1c levels (>7.9% but ≤8.5%), 22% and 31% of patients receiving vildagliptin 50 mg once or twice daily, respectively, and 13% of the placebo group reached their treatment target. Vildagliptin provides additional therapeutic benefit to patients with T2DM inadequately controlled on metformin 2.1 g daily, to achieve therapeutic treatment goals. Reference Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007; 30: 890–895. HbA1c <7.0% BL=baseline; HbA1c=hemoglobin A1c; met=metformin; PBO=placebo; vilda=vildagliptin Primary intention-to-treat population. Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

Προσθήκη Vildagliptin σε Metformin: Σημαντική η μείωση της HbA1c – Παρακολούθηση 52 εβδομάδων Vilda 50 mg daily + met (extension, ITT n=42) PBO + met (extension, ITT n=29) Vilda 50 mg daily + met (core, ITT n=56) 8.4 PBO + met (core, ITT n=51) 8.0 P <0.0001  –1.1 ± 0.2% HbA1c (%) 7.6 P <0.0001 Vildagliptin Add-on to Metformin: Significantly Lowers HbA1c over 52 Weeks This was a 12-week, double-blind, randomized, multicenter, placebo-controlled study comparing the effects of treatment with vildagliptin 50 mg daily (n=56) or placebo (n=51) in patients with type 2 diabetes mellitus (T2DM) continuing a stable dosage of metformin (1500–3000 mg daily).1 The 12-week core study was followed by a 40-week extension which allowed a comparison of the efficacy of vildagliptin 50 mg daily (n=42) compared with placebo (n=29) over 1 year. Mean HbA1c levels decreased progressively during the first 12 weeks of vildagliptin 50 mg daily treatment and then tended to remain stable from Week 12 to Week 52. No real change in HbA1c was observed in the placebo arm during the 12-week core study but HbA1c increased at a rate of 0.07% per month from Week 12 to Week 52. Vildagliptin 50 mg daily as add-on to metformin resulted in significant decreases in HbA1c levels at 12 weeks (P <0.0001) and 52 weeks (P <0.0001) compared with placebo. These results demonstrate that vildagliptin produces clinically meaningful decreases in HbA1c levels for at least 1 year when added to metformin monotherapy in patients with T2DM. Reference 1. Ahrén B, et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2874-2880. 7.2 6.8 −4 4 8 12 16 20 24 28 32 36 40 44 48 52 Week n refers to ITT population. HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin Adapted from Ahrén B, et al. Diabetes Care 2004; 27: 2874-2880.

Προσθήκη Vildagliptin σε Metformin: Όχι αύξηση βάρους Add-on treatment to metformin (2.1 g mean daily) Mean change from BL NS Change in BW (kg) NS Vildagliptin Add-on to Metformin: No Weight Gain Overall This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 In this study, body weight was measured at baseline and at each study visit. Body weight at baseline was similar among the 3 treatment groups.1 Relative to baseline, body weight did not change significantly after 24 weeks of treatment with vildagliptin 50 mg once daily or 50 mg twice daily. In comparison, mean body weight in patients who received placebo decreased by 1.0 kg (P <0.001). Vildagliptin as add-on to metformin causes no weight gain in patients with T2DM. Reference Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30; 890-895. BL BW (kg) * PBO + met (n=130) Vilda 50 mg twice daily + met (n=143) Vilda 50 mg once daily + met (n=143) 93 95 BL=baseline; BW=body weight; met=metformin; PBO=placebo; vilda=vildagliptin NS=not significant vs BL. *P <0.001 vs BL. Primary intention-to-treat population. Bosi E, et al. Diabetes Care 2007; 30: 890-895.

Συνεργική δράση Γλυπτινων και Μετφορμίνης Συνεργική δράση Γλυπτινων και Μετφορμίνης Οι Γλυπτινες αυξάνουν τα ενεργά επίπεδα του GLP-1 κατά 2–4 φορές μέσω αναστολής του ενζύμου DPP-4 1-4 Η Μετφορμίνη αυξάνει τα επίπεδα του GLP-1 κατά πάσα πιθανότητα μέσω αύξησης της σύνθεσης του GLP-1 και όχι μέσω αναστολής του DPP-45-7 Οι Γλυπτινες και η Μετφορμίνη συνεργάζονται για να μεγιστοποιήσουν τα επίπεδα του άθικτου GLP-18 Επίδραση της vildagliptin στα γευματικά επίπεδα του ενεργού GLP-1 σε ασθενείς χωρίς θεραπεία στο παρελθόν έναντι ασθενών που είχαν λάβει θεραπεία με μετφορμίνη * Ενεργό GLP-1 (pmol/L) Συνεργική δράση Vildagliptin και Μετφορμίνης Αρκετές μελέτες έχουν αποδείξει ότι ο αναστολέας της διπεπτιδυλικής πεπτιδάσης-4(DPP-4) vildagliptin οδηγεί σε 2 –4 φορές αύξηση των ενεργών ορμονών ινκρετινών πεπτίδιο που ομοιάζει στη γλυκαγόνη -1 (GLP-1) και το ινσουλινοτρόπο πολυπεπτίδιο που εξαρτάται από τη γλυκόζη (GIP).1-4 Είναι ενδιαφέρον ότι άλλες μελέτες τεκμηρίωσαν ότι η μετφορμίνη αυξάνει τα επίπεδα του GLP-1 σε ασθενείς με σακχαρώδη διαβήτη τύπου 2 (T2DM) μέσω ενός μηχανισμού ανεξάρτητου από την αναστολή του DPP-4 πιθανόν αυξάνοντας τη σύνθεση του GLP-1. Αυτά τα ευρήματα υποδηλώνουν ότι ο συνδυασμός μετφορμίνης με αναστολέα του DPP-4 θα είναι χρήσιμος για τη θεραπεία του T2DM.5,6 Τα δεδομένα που παρουσιάζονται σε αυτή τη γραφική παράσταση προέρχονται από μια μηχανιστική, διπλή-τυφλή ελεγχόμενη με εικονικό φάρμακο μελέτη σε ασθενείς με T2DM. Τα επίπεδα των ορμονών ινκρετινών (GLP-1, GIP) μετρήθηκαν μετά από 6 εβδομάδες θεραπείας με vildagliptin 50 mg δύο φορές την ημέρα ή εικονικό φάρμακο. Η vildagliptin αύξησε τα μεταγευματικά επίπεδα του ενεργού GLP-1 και GIP, αλλά η αύξηση του μεταγευματικού GLP-1 ήταν σημαντικά μεγαλύτερη στους ασθενείς που θεραπευόταν με μετφορμίνη απ’ότι στην υποομάδα ασθενών χωρίς θεραπεία στο παρελθόν.7 Παρόμοια δεδομένα παρατηρήθηκαν επίσης με άλλους αναστολείς του DPP-4.8 Η ανάλυση δείχνει ότι η αναστολή του DPP-4 με τη vildagliptin έχει μεγαλύτερη επίδραση στο ενεργό GLP-1 σε ασθενείς που λαμβάνουν ταυτόχρονα μετφορμίνη απ’ότι σε ασθενείς χωρίς θεραπεία στο παρελθόν, υποδηλώνοντας συνεργική δράση της vildagliptin και της μετφορμίνης για τη μεγιστοποίηση του ενεργού GLP-1. Αυτό το εύρημα ενδεχομένως υπογραμμίζει την ιδιαίτερα αυξημένη αποτελεσματικότητα της vildagliptin στην ελάττωση της HbA1c, της γλυκόζης πλάσματος νηστείας και της μεταγευματικής γλυκόζης όταν προστίθεται σε ασθενείς με T2DM που δεν ελέγχονται επαρκώς μόνο με μετφορμίνη.9,10 Βιβλιογραφία 1. Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255. 2. Ahrén B, et al. J Clin Endocrinol Metab 2004; 89: 2078-2084. 3. Rosenstock J, et al. Diabetes Care 2008; 31: 30-35. 4. Matikainen N, et al. Diabetologia 2006; 49: 2049-2057. 5. Hinke S, et al. Biochem Biophys Ref Commun 2002; 291; 1302-1308. 6. Yasuda N, et al. Biochem Biophys Ref Commun 2002; 298: 779-784. 7. Dunning B, et al. Presented at EASD 2006; abstract 0174. 8. Migova E, et al. Presented at EASD 2007; abstract 0111. 9. Bosi E, et al. Diabetes Care 2007; 30: 890-895. 10. Ahrén B, et al. Diabetes Care 2005; 28: 1936-1940. Vildagliptin σε ασθενείς χωρίς θεραπεία στο παρελθόν (n=5) Vildagliptin σε ασθενείς με θεραπεία μετφορμίνης (n=12) *P <0,05 DPP-4=διπεπτιδυλική πεπτιδάση-4, GLP-1=πεπτίδιο που ομοιάζει στη γλυκαγόνη-1 1Ahrén B, et al. J Clin Endocrinol Metab 2004; 89: 2078-2084; 2Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255; 3Matikainen N, et al. Diabetologia 2006; 49: 2049-2057; 4Rosenstock J, et al. Diabetes Care 2008; 31: 30-35; 5Yasuda N, et al. Biochem Biophys Ref Commun 2002; 298: 779-784; 6Hinke S, et al. Biochem Biophys Ref Commun 2002; 291: 1302-1308; 7Migoya E, et al. Presented at EASD 2007; abstract 0111; 8Dunning B, et al. Presented at EASD 2006; abstract 0174.

Δυσλειτουργία β-κυττάρων Ηπατική υπερπαραγωγή γλυκόζης Ο συνδυασμός γλιπτινών και μετφορμίνης στοχεύει τις 3 παθοφυσιολογικές διαταραχές του ΣΔ τύπου 2 1/Aschner p.2634 Table 1 p.2635 C1 P1 L1-8 2/WPC-JMT-T-102007 p.1 P2 L2-9 p.2 Pcont L1-2 3/Abbasi p.1303 C3 P1 L3-14 4/Inzucchi p.364, C1 P1 L9-L20 5/ Kirpichnikov p.E27 Figure 1 p.E28 Figure 2 6/Zhou p.1173 Figure 7 Οι γλιπτίνες βελτιώνουν τη λειτουργία των β-κυττάρων και αυξάνουν τη σύνθεση και έκκριση ινσουλίνης Οι γλιπτινες έμμεσα μειώνουν την Η.Υ.Γ δια μέσου της καταστολής της γλυκαγόνης από τα α-κύτταρα Η μετφορμίνη μειώνει την Η.Υ.Γ με άμεση δράση στο ήπαρ και μείωση της γλυκογένεσης και γλυκαγονόλυσης Η μετφορμίνη σαν ένας ινσουλινοευαισθητοποιητής (ήπαρ> μυς>. λίπος Δυσλειτουργία β-κυττάρων Ινσουλινοαντίσταση Ηπατική υπερπαραγωγή γλυκόζης The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner The combination of sitagliptin and metformin improves glycaemic control via complementary MOAs. Mechanism of action of sitagliptin1,2: Sitagliptin improves markers of β-cell function and increases insulin synthesis and release Sitagliptin indirectly reduces hepatic glucose overproduction through suppression of glucagon from α cells Mechanism of action of metformin: Metformin increases insulin sensitivity by decreasing the release of free fatty acids from fat to muscle and liver3,4 and by increasing insulin receptor activity in muscle.5 By increasing insulin sensitivity, metformin increases glucose uptake and use in muscle and fat5,6 Metformin decreases hepatic glucose overproduction by directly targeting the liver to decrease gluconeogenesis and glycogenolysis5 In combination, these agents help to improve glycaemic control as a result of their complementary mechanisms of action.2 Sitagliptin improves markers of β-cell function, metformin addresses insulin resistance, and both sitagliptin and metformin address impaired insulin secretion but in different, complementary ways.2,5 The combination of sitagliptin and metformin can be administered as 2 monotherapies or may now be available as JANUMET™†. †Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA Purpose: To describe how metformin and sitagliptin act differently but in a complementary manner. Take-away: The combination of sitagliptin and metformin addresses the 3 core defects of type 2 diabetes with additive efficacy for glycaemic parameters and GLP-1. 1/Aschner p.2634 Table 1 P2635 C1 P1 L1-8 2/WPC-JMT-T-102007 p.1 P2 L2-9 p.1 P1 L1-4 p.2 Pcont L1-2 3/Abbasi p.1303 C3 P1 L3-14 4/Inzucchi p.364, C1 P1 L9-L20 5/ Kirpichnikov p.E27 Figure 1 p.E28 Figure 2 6/Zhou p.1173 Figure 7 HGO=hepatic glucose overproduction. Aschner P et al. Diabetes Care. 2006;29:2632–2637; Abbasi F et al. Diabetes Care. 1998;21:1301–1305; Inzucchi SE. JAMA 2002;287:360–372; Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33; Zhou G et al. J Clin Invest. 2001;108:1167–1174. References 1. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637. 2. Data on file, MSD. 3. Abbasi F, Carantoni M, Chen YD, Reaven GM. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care. 1998;21:1301–1305. 4. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360–372. 5. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med. 2002;137:25–33. 6. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174. 22

Προσθήκη Vildagliptin σε Metformin: Αύξηση της λειτουργικότητας των β-κυττάρων, μείωση της μεταγευματικής υπεργλυκαιμίας β-cell function Adjusted mean change in ISR AUC / glucose AUC * 6.9 7.3 1.6 0.0 2.0 4.0 6.0 8.0 10.0 2-h PPG Adjusted mean change in 2-h PPG (mmol/L) * -1.9 -2.3 -0.1 -3.0 -2.0 -1.0 0.0 Vildagliptin: Enhances β-cell Function and Improves PPG when Metformin Alone is not Sufficient This was a 24-week, double-blind, randomized, multicenter, placebo-controlled study. Vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) were compared in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 After 24 weeks, β-cell function (as measured by insulin secretion rate area under the curve [AUC] / glucose AUC) also improved. There were significant but similar differences for vildagliptin 50 mg once daily and twice daily, respectively, versus placebo (P <0.001 vs placebo).2 Postprandial glucose (PPG) levels were also significantly lower in both vildagliptin groups compared with placebo, with differences from baseline of −1.9 mmol/L for the 50 mg once-daily group and −2.3 mmol/L for the 50 mg twice-daily group, compared with −0.1 mmol/L for placebo (P <0.001). The lack of a dose-response effect on PPG and β-cell function for vildagliptin may be explained by the fact that in both dose groups, 50 mg vildagliptin was given before the breakfast meal test. As vildagliptin produces complete dipeptidyl peptidase-4 inhibition at doses as low as 10 mg for >4 hours, no differences between the 2 groups for this measure would be expected. Vildagliptin provides clinically meaningful, dose-related decreases in PPG and improves β-cell function as add-on therapy in patients with T2DM inadequately controlled on metformin. References 1. Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890-895. 2. Data on file, Novartis Pharmaceuticals, LAF237A2303. AUC=area under the curve; ISR=insulin secretion rate; met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin *P ≤0.001 vs PBO. Bosi E, et al. Diabetes Care 2007; 30: 890-895. Data on file, Novartis Pharmaceuticals, LAF237A2303. Vilda 50 mg once daily + met (n=53) Vilda 50 mg twice daily + met (n=57) PBO + met (n=54)

Vildagliptin: Enhances β-cell Function and Improves PPG when Metformin Alone is not Sufficient 2-h PPG 10.0 -0.1 * 0.0 * 8.0 7.3 6.9 6.0 -1.0 Adjusted mean change in 2-h PPG (mmol/L) Adjusted mean change in ISR AUC / glucose AUC 4.0 -1.9 -2.0 Vildagliptin: Enhances β-cell Function and Improves PPG when Metformin Alone is not Sufficient This was a 24-week, double-blind, randomized, multicenter, placebo-controlled study. Vildagliptin 50 mg once daily (n=143), vildagliptin 50 mg twice daily (n=143), or placebo (n=130) were compared in patients with type 2 diabetes mellitus (T2DM) continuing a stable metformin dose regimen (mean dose 2.1 g daily) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 After 24 weeks, β-cell function (as measured by insulin secretion rate area under the curve [AUC] / glucose AUC) also improved. There were significant but similar differences for vildagliptin 50 mg once daily and twice daily, respectively, versus placebo (P <0.001 vs placebo).2 Postprandial glucose (PPG) levels were also significantly lower in both vildagliptin groups compared with placebo, with differences from baseline of −1.9 mmol/L for the 50 mg once-daily group and −2.3 mmol/L for the 50 mg twice-daily group, compared with −0.1 mmol/L for placebo (P <0.001). The lack of a dose-response effect on PPG and β-cell function for vildagliptin may be explained by the fact that in both dose groups, 50 mg vildagliptin was given before the breakfast meal test. As vildagliptin produces complete dipeptidyl peptidase-4 inhibition at doses as low as 10 mg for >4 hours, no differences between the 2 groups for this measure would be expected. Vildagliptin provides clinically meaningful, dose-related decreases in PPG and improves β-cell function as add-on therapy in patients with T2DM inadequately controlled on metformin. References 1. Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890-895. 2. Data on file, Novartis Pharmaceuticals, LAF237A2303. -2.3 2.0 * 1.6 -3.0 * 0.0 AUC=area under the curve; ISR=insulin secretion rate; met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin *P ≤0.001 vs PBO. Bosi E, et al. Diabetes Care 2007; 30: 890-895. Data on file, Novartis Pharmaceuticals, LAF237A2303. Vilda 50 mg once daily + met (n=53) Vilda 50 mg twice daily + met (n=57) PBO + met (n=54)

Η Vildagliptin εξίσου δραστική με την Pioglitazone όταν προστέθηκε σε Metformin FU: 24εβδομ. Add-on treatment to metformin (2.0 g mean daily) Overall Mean BL ~8.4% HbA1c >9% Mean BL ~9.7% n= 264 246 63 58 change in HbA1c (%) Adjusted mean Vildagliptin: as Effective as Pioglitazone when Added to Metformin This 24-week, multicenter, double-blind, randomized, active-controlled study compared the efficacy and safety of vildagliptin 50 mg twice daily (n=295) and pioglitazone 30 mg once daily (n=281) in patients with inadequate glycemic control (HbA1c 7.5–11%) while receiving a stable metformin dose (>1500 mg daily). The primary efficacy assessment was the change from baseline in HbA1c at Week 24. Non-inferiority of vildagliptin to pioglitazone in decreasing HbA1c was assessed (see slide for definition). Secondary efficacy parameters included fasting plasma glucose, fasting lipids, and body weight. Vildagliptin 50 mg twice daily demonstrated comparable efficacy with pioglitazone when added to metformin. The adjusted mean changes in HbA1c were −0.9% and −1.0% for vildagliptin- and pioglitazone-treated patients, respectively, with the non-inferiority of vildagliptin to pioglitazone established at both 0.4 and 0.3% margins. In patients with high baseline HbA1c (>9%), larger HbA1c reductions of −1.5% were obtained with both vildagliptin and pioglitazone treatments as add-on to metformin. This study has demonstrated that in patients with T2DM inadequately controlled with metformin monotherapy, vildagliptin 50 mg twice daily is as effective as pioglitazone when added to metformin. Reference 1. Bolli G, et al. Efficacy and tolerability of vildagliptin versus pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab 2008; 10: 82-90. Non-inferior* Pio 30 mg once daily + met Vilda 50 mg twice daily + met BL=baseline; HbA1c=hemoglobin A1c; met=metformin; pio=pioglitazone; vilda=vildagliptin Per protocol population. Non-inferiority of vildagliptin to pioglitazone established at both 0.4% and 0.3% margins, 95% confidence interval=(0.1, 0.3). Adjusted mean change derived from analysis of covariance model. Bolli G, et al. Diabetes Obes Metab 2008; 10: 82-90.

Vilda 50 mg twice daily + met Vildagliptin vs Pioglitazone as Add-ons to Metformin: Efficacy Maintained over 1 Year Duration: 52 weeks Add-on to met: vilda vs pio Add-on to Met: Vilda vs Pio in T2DM patients 9.0 24-week primary analysis 8.5 Mean HbA1c (%) 8.0 7.5 Vildagliptin vs Pioglitazone as Add-ons to Metformin: Efficacy Maintained over 1 Year This multicenter, randomized, active-controlled study compared the efficacy and safety of vildagliptin 50 mg twice daily (n=295) and pioglitazone 30 mg once daily (n=281) in patients with inadequate glycemic control (HbA1c 7.5–11%) while receiving a stable metformin dose (≥1500 mg daily).1 There was a double-blind, 24-week phase to assess efficacy and safety,1 followed by a 28-week phase to assess long-term safety.2 The primary efficacy assessment in the first phase of the study was the change from baseline in HbA1c at Week 24.1,2 Initially, the mean HbA1c reduced at a more rapid rate in the vildagliptin group than in the pioglitazone group.1,2 By week 24, mean HbA1c had plateaued in both groups; there was a slight rise by Week 40 in the vildagliptin group but Week 52 levels of HbA1c in the two groups were comparable.2 Over a 1-year period, HbA1c levels decreased at a more rapid initial rate in vildagliptin- treated patients compared with pioglitazone-treated patients. Efficacy was maintained in vildagliptin- and pioglitazone-treated patients over a 1-year period.2 References Bolli G, et al. Efficacy and tolerability of vildagliptin versus pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2008; 10: 82–90. Bolli G, et al. Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Obes Metab (in press). 7.0 −4 4 12 16 24 32 40 52 Week Intention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281) HbA1c=haemoglobin A1c; met=metformin; pio=pioglitazone; T2DM=type 2 diabetes mellitus; vilda=vildagliptin Bolli G et al. Diabetes Obes Metab, in press. Vilda 50 mg twice daily + met Pio 30 mg once daily + met

Όχι πρόσκτηση βάρους από την προσθήκη Vildagliptin σε Metformin σε αντίθεση με την προσθήκη Pioglitazone All patients Mean BL ~91.8 kg BMI >35 kg/m2 Mean BL ~110.4 kg n= 264 246 73 70 * Pio 30 mg once daily + met Vilda 50 mg twice daily + met * Adjusted mean change in body weight (kg) to Week 24 Vildagliptin Add-on to Metformin: No Weight Gain This 24-week, multicenter, double-blind, randomized, active-controlled study compared vildagliptin 50 mg twice daily (n=295) and pioglitazone 30 mg once daily (n=281) in patients with inadequate glycemic control (HbA1c 7.5–11%) on a stable metformin dose (>1500 mg daily). Baseline body weight was similar in the 2 groups. Weight remained stable with vildagliptin throughout the 24-week study, whereas patients on pioglitazone had a progressive increase in weight. The between-treatment difference in mean change in body weight was of −1.6 kg (P <0.001 vs pioglitazone). In patients who were severely obese (≥35 mg/m2) at baseline, a more substantial weight increase from baseline of 2.6 kg was observed with pioglitazone treatment. The corresponding change in vildagliptin-treated patients was 0.1 kg, representing a significant between-treatment difference in body weight (P <0.001). Vildagliptin 50 mg twice daily added to metformin is as effective as a thiazolidinedione without weight gain. Pioglitazone is associated with significant weight gain that is more pronounced in severely obese patients. Reference 1. Bolli G, et al. Efficacy and tolerability of vildagliptin versus pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab 2008; 10: 82-90. BL=baseline; BMI=body mass index; met=metformin; pio=pioglitazone; vilda=vildagliptin *P <0.001 vs pioglitazone. Per protocol population. Adjusted mean change derived from analysis of covariance model. Bolli G, et al. Diabetes Obes Metab 2008; 10: 82-90.

Η αποτελεσματικότητα και η ασφάλεια της Vildagliptin vs Glimepiride σε ΣΔ ΙΙ ανεπαρκώς ρυθμιζόμενο με Metformin Fu = 52 εβδομάδες HbA1c HbA1c Υπογλυκαιμία Σωματικό βάρος Kg Vildagliptin Vildagliptin Glimepiride 20% Glimepiride 16% 7,3% 7 0,48 0,53 2 1,70 6 1 0,5 1,7% 10 20 30 40 52 -0,33 Εβδομάδες Ferrannini et al, Diab. Obes. And Metab 2009;11:157-166

Head-to-head Study: Vildagliptin vs SU in Add-on to Metformin – Interim Analysis at 1 Year Study purpose: to demonstrate long-term efficacy and safety of add-on therapy with vildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoing metformin monotherapy in a randomized, double-blind, multicenter study Interim analysis: to demonstrate non-inferiority of vildagliptin vs glimepiride at 1 year Target population: patients with T2DM inadequately controlled on a stable metformin monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%) n=1396: Vildagliptin 50 mg twice daily + metformin N=2789* Head-to-Head Study: Vildagliptin vs SU in Add-on to Metformin – Interim Analysis at 1 Year This multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily (n=1396) and glimepiride up to 6 mg daily (n=1393) in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (>1500 mg daily). An interim analysis was undertaken at 1 year.1 The primary efficacy assessment was the change from baseline in HbA1c. Secondary efficacy parameters included fasting plasma glucose and body weight. Safety assessments included monitoring of adverse events. Reference Ferrannini E, et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2008; Epub ahead of print. n=1393: Glimepiride up to 6 mg once daily + metformin Metformin 1-year interim analysis 4 weeks 104 weeks *Randomized population. HbA1c=hemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print. 56

Vildagliptin: as Effective as Glimepiride when Added to Metformin at 52 Weeks Duration: 52 weeks Add-on to met: vilda vs glim Add-on Treatment to Metformin (~1.9 g Mean Daily) Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin Mean HbA1c (%) −0.4% Vildagliptin: as Effective as Glimepiride when Added to Metformin at 52 weeks This 1-year interim analysis of a multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily and glimepiride up to 6 mg daily in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (~1.9 g daily).1 There was a reduction in HbA1c in both groups (vildagliptin −0.4%; glimepiride −0.5%). The between-group difference in adjusted mean change from baseline at 52 weeks was 0.09%. Non-inferiority of vildagliptin to glimepiride was achieved (97.5% confidence interval [CI] 0.02,0.16) for HbA1c based on the predefined non-inferiority margin of the upper limit of the 97.5% CI not exceeding 0.3%. After 52 weeks of treatment, vildagliptin was as effective as glimepiride when added to metformin. Reference Ferrannini E et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes, Obes Metab 2008; Epub ahead of print. NI: 97.5% CI (0.02, 0.16) −0.5% Time (Weeks) CI=confidence interval; glim=glimepiride; HbA1c=hemoglobin A1c; met=metformin; NI=not inferior; vilda=vildagliptin Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print. 57

Vildagliptin vs Glimepiride: Hypoglycemic Events in Add-on to Metformin Treatment Duration: 52 weeks Add-on to met: vilda vs glim Patients with >1 Hypos (%) Number of Hypoglycemic Events Severe Events (Grade 2 and Suspected Grade 2) n = 1389 1383 1389 1383 1389 1383 Incidence (%) No. of Events No. of Events Vildagliptin vs Glimepiride: Hypoglycemic Events in Add-on to Metformin Treatment This 1-year interim analysis of a multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily and glimepiride up to 6 mg daily in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (~1.9 g daily).1 1.7% of patients in the vildagliptin group (n=1389) and 16.2% of patients in the glimepiride group (n=1383) experienced ≥1 hypoglycemic events. There were 39 hypoglycemic events in the vildagliptin group and 554 in the glimepiride group. There were no severe (grade 2 and suspected grade 2) hypoglycemic events in the vildagliptin group and 10 severe hypoglycemic events in the glimepiride group. There were fewer hypoglycemic events in the vildagliptin group over the 52-week period. Reference Ferrannini E et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2008; Epub ahead of print. Glimepiride up to 6 mg once daily + metformin Vildagliptin 50 mg twice daily + metformin Glim=glimepiride; met=metformin; vilda=vildagliptin Safety population. Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print. 58

Vildagliptin: No Weight Gain Duration: 52 weeks Add-on to met: vilda vs glim Add-on Treatment to Metformin (~1.9 g Mean Daily) Body Weight (kg) −1.8 kg difference Vildagliptin: No Weight Gain This 1-year interim analysis of a multicenter, randomized, double-blind active-controlled study compared the long-term efficacy and safety of vildagliptin 50 mg twice daily and glimepiride up to 6 mg daily in patients with inadequate glycemic control (HbA1c 6.5–8.5%) while receiving a stable metformin dose (~1.9 g daily).1 During the study period the weight of patients taking vildagliptin had remained stable, whereas those who had taken glimeripride had experienced an increase in weight. The difference between groups after 52 weeks was 1.8 kg.2 After 52 weeks of treatment, there was no weight gain in patients receiving vildagliptin 50 mg twice daily + metformin. References Ferrannini E et al. 52-week efficacy and safety of vildagliptin versus glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2008; Epub ahead of print. Data on file, Novartis Pharmaceuticals, LAF237A2308. Time (Weeks) Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin Glim=glimepiride; met=metformin; vilda=vildagliptin Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print. Data on file, Novartis Pharmaceuticals, LAF237A2308. 59

Single-pill Combinations May Improve Compliance Low compliance in chronic diseases such as diabetes may adversely affect clinical outcomes SPCs can reduce risk of non-compliance by up to 26%1 Switching to an SPC from combination therapy improves treatment adherence2 Improved glycemic control was obtained with an SPC in patients with T2DM3 * 77% 54% Adherence Rate (%) Single-pill Combinations May Improve Compliance A recent meta-analysis of single-pill combinations (SPCs) in managing chronic disease found that non-compliance to medication regimens is reduced by 24–26% with SPCs compared with drugs administered separately.1 This is important as low compliance rates in patients with conditions such as diabetes can be detrimental to clinical outcomes. A study comparing an SPC with individual medications in diabetes found a significant improvement in adherence following a switch to an SPC from a free combination (77% vs 54%). Patients previously on monotherapy and requiring an additional agent had higher adherence rates to a SPC than to combination therapy.2 In patients with type 2 diabetes mellitus, a SPC of metformin and glyburide resulted in a significantly greater decrease in HbA1c than co-administration of glyburide and metformin, particularly in patients with baseline HbA1c of at least 8%.3 These studies suggest that SPCs may improve patient compliance with treatment, which can translate to improved clinical outcomes. References Bangalore S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007; 120: 713–719. Melikian C, et al. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Clin Ther. 2002; 24: 460–467. Blonde L, et al. Greater reductions in A1C in type 2 diabetic patients new to therapy with glyburide/metformin tablets as compared to glyburide co-administered with metformin. Diabetes Obes Metab. 2003; 5: 424–431. Free Combination (n=1815)† Single-pill Combination (n=105)† SPC=single-pill combination; T2DM=type 2 diabetes mellitus P <0.001 vs combination therapy. †Previously treated patients receiving glyburide or metformin monotherapy. 1Bangalore S, et al. Am J Med. 2007; 120: 713–719. 2Melikian C, et al. Clin Ther. 2002; 24: 460–467; 3Blonde L, et al. Diabetes Obes Metab. 2003; 5: 424–431.

Initial Combination of Vildagliptin and Metformin: Study Design and Objectives Primary objective: to demonstrate efficacy of single-pill combination therapy of vildagliptin and metformin compared with individual monotherapy in drug-naïve patients with T2DM in a multicenter, randomized, double-blind, active-controlled study Target population: drug-naïve patients with T2DM (HbA1c 7.5–11%) Screening Titration Maintenance n=300 Vildagliptin 50 mg bid Vilda 50 mg qd n=294 Met 1000 mg AM Met 500 mg PM Metformin 1000 mg bid Met 500 mg qd Met 500 mg bid N=1179* n=290 Initial Combination Study of Vildagliptin + Metformin – Design and Objectives This was a 24-week, double-blind, randomized, multicenter, active-controlled study in drug-naïve patients with type 2 diabetes mellitus, HbA1c 7.5–11% at baseline (2302 study).1 Patients received vildagliptin 50 mg daily rising to 50 mg twice daily (n=300), or metformin 500 mg daily rising to 1000 mg twice daily (n=294), or fixed-combination vildagliptin/metformin 50/500 mg daily rising to 50/500 mg twice daily (n=290), or fixed-combination vildagliptin/metformin 50/500 mg daily rising to 50/1000 mg twice daily (n=295). Study medication was increased to the next dose level when glycemic control was attained (based on a fasting fingerstick capillary glucose measurements). The primary efficacy variable was change from baseline in HbA1c at 24 weeks. Secondary efficacy variables included change from baseline in fasting plasma glucose and weight after 24 weeks of treatment. Reference 1. Bosi E, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naïve patients with type 2 diabetes mellitus. Diabetes Obes Metab (in press). 2. Data on file, Novartis Pharmaceuticals, LMF237A2302. Low dose: vilda / met 50/500 mg bid Vilda / met 50/500 mg qd n=295 High dose: vilda / met 50/1000 mg bid 50/500 mg bid 50/1000 mg AM 50/500 mg PM Vilda/met 50/500 qd 2 weeks 2 weeks 2 weeks 2 weeks 18 weeks 24 weeks *Randomized population. HbA1c=hemoglobin A1c; met=metformin; T2DM=type 2 diabetes mellitus; vilda=vildagliptin Bosi E et al, Diabetes Obes Metab, in press; Data on file, Novartis Pharmaceuticals, LMF237A2302. 61

Initial Combination of Vildagliptin + Metformin Provides Significantly more HbA1c Reductions than the Monotherapies Duration: 24 weeks Vilda + met vs mono Change from Baseline to End Point Mean Baseline HbA1c ~8.6% n = 287 285 277 285 Mean Change in HbA1c (%) Initial Combination of Vildagliptin + Metformin Provides Significantly more HbA1c reductions than the monotherapies This was a 24-week, double-blind, randomized, multicenter, active-controlled study in drug-naïve patients (2302 study).1 Patients received vildagliptin monotherapy (n=287), metformin monotherapy (n=285), low-dose fixed-combination vildagliptin/metformin (n=277), or high-dose fixed-combination vildagliptin/metformin (n=285). Mean baseline HbA1c was ~8.6%. At 24 weeks, reductions from baseline in mean HbA1c were: vildagliptin monotherapy −1.1%; metformin monotherapy −1.4%; low-dose fixed-combination vildagliptin/metformin; −1.6%, or high-dose fixed-combination vildagliptin/metformin −1.8%. At 24 weeks, reductions in HbA1c levels in both the low- and high-dose fixed-combination groups were statistically significantly greater than in the monotherapy groups (P ≤0.004). Reference 1. Bosi E, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naïve patients with type 2 diabetes mellitus. Diabetes Obes Metab (in press). 2. Data on file, Novartis Pharmaceuticals, LMF237A2302. P <0.001 P=0.004 Vilda + HD met (50/1000 mg bid) Vilda + LD met (50/500 mg bid) Met 1000 mg bid Vilda 50 mg bid P <0.001 P <0.001 Intention-to-treat population. HbA1c=hemoglobin A1c; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin Bosi E et al, Diabetes Obes Metab, in press; Data on file, Novartis Pharmaceuticals, LMF237A2302. 62

High BL Open-label Sub-study b Initial Combination of Vildagliptin and Metformin Effective across the Hyperglycemia Spectrum (Data from Core Study and Open-label Sub-study) Duration: 24 weeks Vilda + met vs mono Change from BL to EP High BL Open-label Sub-study b Overall* Subgroups by BL HbA1ca >8% >9% ≥10% >11% BL mean= n = ~8.7% 285 ~9.2% 201 ~9.9% 96 ~10. 6% 35 ~12. 1% 86 Mean Change in HbA1c (%) Initial Combination of Vildagliptin and Metformin: Effective across the Hyperglycemia Spectrum This was a 24-week, double-blind, randomized, multicenter, active-controlled study in drug-naïve patients.1,2 Patients received vildagliptin monotherapy (n=287), metformin monotherapy (n=285), low-dose fixed-combination vildagliptin/metformin (n=277), or high-dose fixed-combination vildagliptin/metformin (n=285). In an open-label sub-study, patients with a high baseline HbA1c received vildagliptin 100 mg daily as an add-on to metformin 2000 mg.1,3 Mean baseline HbA1c was ~8.6% overall. In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily, n=285) the reduction in HbA1c at 24 weeks was −1.8%. In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily) with baseline HbA1c >8% (mean 9.2%, n=201) the reduction in HbA1c at 24 weeks was −2.1%. In patients receiving high-dose fixed-combination vildagliptin/metformin (50/1000 mg twice daily) with baseline HbA1c >9% (mean 9.9%, n=96) the reduction in HbA1c at 24 weeks was −2.6%. There was a greater reduction in HbA1c in patients with higher initial HbA1c (>8%) who received high-dose fixed-combination vildagliptin/metformin compared with patients HbA1c 7.5–11% at baseline. References 1. Bosi E, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naïve patients with type 2 diabetes mellitus. Diabetes Obes Metab (in press). 2. Data on file, Novartis Pharmaceuticals, LMF237A2302. 3. Data on file, Novartis Pharmaceuticals, CLMF237A2302S1. * High-dose vilda + met (50/1000 mg twice daily)c Vilda 100 mg daily** + met 2000 mg daily open-label sub-study (P <0.001 vs BL)d *P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen. Intent-to-treat population. aRaw mean change from baseline; bLS (least-square) mean change from baseline. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin. Bosi E et al, Diabetes Obes Metab, in press; Data on file, Novartis Pharmaceuticals, bLMF237A2302 and dLMF237A2302S1.

ΙΙΙ. ΣΕ ΣΥΝΔΥΣΜΟ ΜΕ ΣΟΥΛΦΟΝΥΛΟΥΡΙΑ

In add-on to SU, vildagliptin 50mg qd significantly reduces HbA1c Add-on treatment to an SU (glimepiride 4 mg once daily) 9.0 Vilda 50 mg once daily + glim (n=132) Vilda 50 mg twice daily + glim (n=132) 8.8 PBO + glim (n=144) 8.6 8.4 Mean HbA1c (%) 8.2 * Vildagliptin: Reduction in HbA1c over 24 Weeks This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared vildagliptin 50 mg once daily (n=132), 50 mg twice daily (n=132), or placebo (n=144) added to glimepiride (4 mg daily) in patients with type 2 diabetes mellitus (T2DM) not adequately controlled with a sulfonylurea (HbA1c 7.5–11%).1 Vildagliptin as add-on to glimepiride statistically significantly decreased HbA1c levels at 24 weeks compared with placebo. The between-treatment difference in adjusted mean change in HbA1c was −0.6% (P <0.001) with vildagliptin 50 mg once daily and −0.7% (P <0.001) with vildagliptin 50 mg twice daily. HbA1c reduction reflects, in essence, the sum of the effects on postprandial glucose (PPG) and fasting plasma glucose (FPG). Since there was no significant effect of vildagliptin to reduce FPG, any dose-response for HbA1c reduction would require that 50 mg twice daily exert a larger effect than 50 mg once daily on PPG. There is a simple explanation for the lack of a differential effect of 50 once and 50 mg twice daily. Vildagliptin completely inhibits dipeptidyl peptidase-4 (DPP-4) at doses as low as 10 mg for ≥4 hours. Both vildagliptin doses were given before the breakfast meal test and so elicited essentially the same level of DPP-4 inhibition throughout the post-meal sampling period. Because a single 50 mg vildagliptin dose elicits >80% DPP-4 inhibition for ≥12 hours, any benefit from the 50 mg twice daily dose would come from decreasing overnight glucose levels rather than from reduced PPG after the evening meal. These results indicate that vildagliptin as add-on to glimepiride produces clinically meaningful reductions in HbA1c levels in patients with T2DM not adequately treated with a sulfonylurea. Reference 1. Garber A, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulfonylurea. Diabetes Obes Metab 2007; [Epub]. 8.0 −0.6% vs PBO −0.7% vs PBO 7.8 * 7.6 −4 4 8 12 16 20 24 Time (weeks) Glim=glimepiride; PBO=placebo; SU=sulfonylurea; vilda=vildagliptin *P <0.001 vs PBO. Primary intention-to-treat population. Garber A, et al. Diabetes Obes Metab 2007; [Epub].

Vildagliptin Add-on to an SU: Efficacy in Elderly Patients and those with Poorly Controlled T2DM Add-on treatment to an SU (glimepiride 4 mg once daily) BL >9.0% >65 years n= 32 4 41 38 BL= 9.8 9.8 8.5 8.5 Change in HbA1c (%) Vildagliptin Add-on to an SU: Efficacy in Elderly Patients and those with Poorly Controlled T2DM This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg once daily (n=132) and placebo (n=144) added to glimepiride (4 mg daily) in patients with type 2 diabetes mellitus (T2DM) not adequately controlled with a sulfonylurea (HbA1c 7.5–11%).1 In subgroup analyses of patients with high baseline HbA1c (>9.0%), reductions of −1.0% and −0.9% were observed with vildagliptin 50 mg once daily. In subgroup analyses of elderly patients, HbA1c levels decreased after 24 weeks with vildagliptin 50 mg once daily (−0.7 ± 0.1%). Baseline levels were similar in both treatment groups for the subgroup analyses. These results indicate that vildagliptin 50 mg once daily as add-on to glimepiride results in clinically meaningful HbA1c reductions in patients with high baseline HbA1c and in elderly patients with T2DM not adequately treated with a sulfonylurea. References 1. Garber A, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulfonylurea. Diabetes Obes Metab 2007; [Epub]. 2. Data on file, Novartis Pharmaceuticals, LAF237A2305. Vilda 50 mg once daily + glim PBO + glim BL=baseline; glim=glimepiride; HbA1c=hemoglobin A1c; PBO=placebo; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; vilda=vildagliptin Primary intention-to-treat population. Garber A, et al. Diabetes Obes Metab 2007; [Epub].

Vildagliptin: Low incidence of Hypoglycemic Events in Add-on to SU Vilda add-on pio vs PBO Vilda add-on SU vs PBO Vilda 50 mg once daily + pio 45 mg N=146 n (%) Vilda 50 mg twice daily + pio 45 mg N=158 n (%) Placebo + pio 45 mg N=158 n (%) Vilda 50 mg once daily + glim N=170 n (%) Placebo + glim N=176 n (%) With >1 hypoglycemic events 1 (0.6) 3 (1.9) 2 (1.2) Discontinued due to hypoglycemic events With grade 2 hypoglycemic events Patients Vildagliptin Add-on to TZD or SU: Hypoglycemic Events up to 24 Weeks Hypoglycemic events were defined as: (a) symptoms patient is able to self-treat, and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2); and (c) symptoms patient is unable to self-treat, and no plasma glucose value available (suspected grade 2).1 In two 24-week studies where patients were treated with vildagliptin 50 mg once or twice daily as add-on to pioglitazone1, and 50 mg once daily as add-on to glimperide2, hypoglycemic events were generally mild (grade 1) and infrequent. In the add-on to pioglitazone study, only one patient (0.6%) receiving vildagliptin (50mg twice daily) experienced ≥1 hypoglycemic events, compared with three patients (1.9%) in the placebo group. The incidence in the sulfonylurea add-on study was 1.2% and 0.6% for the vildagliptin and placebo groups, respectively. There were no severe hypoglycemic events in either study and no patients were discontinued due to a hypoglycemic event. These safety data show that the risk for hypoglycemia is very low and comparable with placebo for vildagliptin as an add-on to pioglitazone. The risk for hypoglycemia is slightly higher than placebo for vildagliptin as an add-on to glimepiride for patients with type 2 diabetes mellitus. References Data on file, Novartis Pharmaceuticals, CLAF237A2304. Data on file, Novartis Pharmaceuticals, CLAF237A2305. Hypoglycemic events are defined as: (a) symptoms patient is able to self-treat, and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2); and (c) symptoms patient is unable to self-treat, and no plasma glucose value available (suspected grade 2). Glim=glimepiride; PBO=placebo; pio=pioglitazone; SU=sulfonylurea; TZD=thiazolidinedione; vilda=vildagliptin Data on file, Novartis Pharmaceuticals, CLAF237A2304, 2305.

ΙV. ΣΕ ΣΥΝΔΥΣΜΟ ΜΕ ΓΛΙΤΑΖΟΝΗ

Vildagliptin Add-on to Maximum-dose Pioglitazone: Significant Reduction of HbA1c over 24 Weeks Duration: 24 weeks Add-on to pio: vilda vs PBO Add-on Treatment to Pioglitazone 45 mg Daily Mean HbA1c reduction from BL ~8.7% Change in HbA1c (%) Vildagliptin Add-on to Maximum-dose Pioglitazone: Significant Reduction of HbA1c over 24 Weeks This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared vildagliptin 50 mg once daily (n=124), vildagliptin 50 mg twice daily (n=136), or placebo (n=138) in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with thiazolidinedione monotherapy (HbA1c 7.5–11%).1 All patients received pioglitazone 45 mg daily throughout the study. Treatment with vildagliptin 50 mg once daily or 50 mg twice daily resulted in statistically significant decreases in HbA1c levels at 24 weeks compared with placebo.1 The data demonstrate that vildagliptin as add-on to pioglitazone is effective in decreasing HbA1c levels by a clinically meaningful degree in patients with T2DM inadequately controlled with a maximum dose of prior thiazolidinedione monotherapy. Reference Garber A, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007; 9: 166–174. * * Vilda 50 mg once daily + pio (n=124) Vilda 50 mg twice daily + pio (n=136) PBO + pio 45 mg daily (n=138) BL=baseline; HbA1c=hemoglobin A1c; PBO=placebo; pio=pioglitazone; vilda=vildagliptin Primary intention-to-treat population. *P <0.001 vilda + pio vs PBO + pio. Garber A, et al. Diabetes Obes Metab. 2007; 9: 166–174. 69

Initial Combination with Vildagliptin and Pioglitazone: Significant HbA1c Reduction Duration: 24 weeks Initial combination with pio Mean HbA1c Reduction from BL ~8.7% 0.0 −0.5 −1.0 Change in HbA1c (%) −1.1 −1.5 −1.4 Initial Combination with Vildagliptin and Pioglitazone: Significant HbA1c Reduction This 24-week, double-blind, randomized, active-controlled, parallel-group, multicenter study compared the effects of initial vildagliptin plus pioglitazone combination treatment with component monotherapy in drug-naïve patients with type 2 diabetes mellitus (T2DM) with inadequate glycemic control (HbA1c 7.5–11%).1 Patients were randomized to receive vildagliptin 100 mg once daily (n=154), pioglitazone 30 mg once daily (n=161), low-dose combination treatment (vildagliptin 50 mg once daily plus pioglitazone 15 mg daily, n=144), or high-dose combination treatment (vildagliptin 100 mg once daily plus pioglitazone 30 mg daily, n=148). HbA1c levels had decreased in all treatment groups at the 24-week assessment.1 However, the adjusted mean change in HbA1c from baseline to end point was significantly greater in the high-dose group (−1.9 ± 0.1%, P <0.001) and the low-dose group (−1.7 ± 0.1%, P=0.039) compared with patients receiving pioglitazone monotherapy. These results show that the initial combination of vildagliptin and pioglitazone simultaneously addresses the multiple defects in T2DM by means of complementary mechanisms and appears to be an effective way to achieve good glycemic control. Reference Rosenstock J, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007; 9: 175–185. −1.7 −2.0 −1.9 * ** Pio 30 mg once daily (n=157) Vilda 100 mg once daily + pio 30 mg once daily (n=146) Vilda 100 mg once daily (n=150) Vilda 50 mg once daily + pio 15 mg once daily (n=139) −2.5 BL=baseline; HbA1c=hemoglobin A1c; pio=pioglitazone; vilda=vildagliptin Intention-to-treat population. *P <0.05 (vs pio 30 mg); **P <0.001 Rosenstock J, et al. Diabetes Obes Metab. 2007; 9: 175–185. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. 70

V. ΣΕ ΣΥΝΔΥΣΜΟ ΜΕ ΙΝΣΟΥΛΙΝΗ

Vildagliptin Add-on to Insulin: Study Design and Objective Objective: to demonstrate superior HbA1c reduction of vildagliptin + insulin vs placebo + insulin Target population: T2DM patients treated with insulin; HbA1c 7.5–11% n=144: Vildagliptin 50 mg twice daily + insulin Insulin N=296* n=152: Placebo + insulin Vildagliptin Add-on to Insulin: Study Design and Objective This was a 24-week, double-blind, randomized, multicenter, placebo-controlled study comparing the effects of treatment with vildagliptin 50 mg twice daily (n=144) or placebo (n=152) in patients with type 2 diabetes mellitus treated with insulin (for at least 3 months, at a dose of >30 U/day for a minimum of 4 weeks) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 The primary end point of this study was to determine whether vildagliptin as add-on to insulin treatment was more effective in reducing HbA1c levels than insulin monotherapy. This was evaluated using the change from baseline in HbA1c at study end point. Reference Fonseca V, et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007; 50: 1148–1155. 4 weeks 24 weeks HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus *Patient number refers to randomized patients; primary intention-to-treat population n=290. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155. 72

Vildagliptin Add-on to Insulin: Significant Reduction in HbA1c and Fewer Hypoglycemic Events Duration: 24 weeks Add-on to insulin: vilda vs PBO Add-on Treatment to Insulin Overall Mean BL = 8.4% >65 Years Mean BL = 8.4% n = 140 149 42 41 Change in HbA1c (%) PBO + insulin Vilda 50 mg twice daily + insulin * ** No. of Events No. of Severe Events * Vildagliptin Add-on to Insulin: Significant Reduction in HbA1c and Fewer Hypoglycemic Events This 24-week, double-blind, randomized, multicenter, placebo-controlled study compared the effects of treatment with vildagliptin 50 mg twice daily (n=144) or placebo (n=152) in patients with type 2 diabetes mellitus (T2DM) treated with insulin (>30 U/day) but achieving inadequate glycemic control (HbA1c 7.5–11%).1 Mean daily insulin dose was similar in both the vildagliptin 50 mg twice-daily (81 U) and placebo (82 U) treatment groups. Overall, vildagliptin 50 mg twice daily as add-on to insulin significantly reduced HbA1c levels compared with both baseline and placebo at 24 weeks. The placebo-adjusted mean change in HbA1c from baseline to end point was −0.3% (P=0.01). In patients aged ≥65 years, there was a significant decrease of −0.7% in mean HbA1c levels compared with baseline (P <0.001). The placebo-adjusted mean change in HbA1c from baseline to end point was −0.6% (P=0.001). Significantly fewer patients who received vildagliptin 50 mg twice daily as add-on to insulin treatment experienced hypoglycemic events (22.9% of patients reported 113 events; P <0.01) compared with placebo (29.6% of patients reported 185 events). There were no severe hypoglycemic events in the vildagliptin group compared with six events in the placebo group. One hypothesis for these favorable effects is that dipeptidyl peptidase-4 (DPP-4) inhibitors can restore pancreatic α-cell function, improving glucose sensing and response to changes in plasma glucose levels. Additionally, through DPP-4 inhibition, vildagliptin extends glucagon-like peptide-1 activity to increase glucagon levels and enhance the stimulatory effect of low glucose levels on the α-cell.1 These results demonstrate that vildagliptin as add-on to insulin produces significant decreases in HbA1c levels in the general population of patients with T2DM and in elderly patients with T2DM. Furthermore, despite lowering HbA1c levels, vildagliptin as add-on to insulin treatment reduces the incidence of hypoglycemic events and may protect patients from severe hypoglycemia. Reference 1. Fonseca V, et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007; 50: 1148–1155. 185 200 10 160 ** 113 8 6 120 No. of Severe Events No. of Events 6 80 4 40 2 PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups. Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155. 73

ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ ΑΠΟ ΤΗ ΧΡΗΣΗ ΤΗΣ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗΣ

Η επίπτωση των ανεπιθύμητων ενεργειών στις συνδυαστικές μελέτες της Vildagliptin Επιπλοκές Vilda 50 mg once daily N=693 n (%) Vilda 50 mg twice daily N=2343 n (%) Total PBO N=718 n (%) Total comp N=2387 n (%) Συνολικά 411 (59.3) 1466 (62.6) 468 (65.2) 1611 (67.5) Ρινοφαρυγγίτιδα 44 (6.3) 126 (5.4) 41 (5.7) 134 (5.6) Ίλιγγος 33 (4.8) 125 (5.3) 43 (6.0) 207 (8.7) Κεφαλαλγία 34 (4.9) 21 (2.9) 114 (4.8) Γριππώδης συνδρομή 18 (2.6) 86 (3.7) 40 (5.6) 83 (3.5) Ατονία 22 (3.2) 85 (3.6) 28 (3.9) 146 (6.1) Τρομος 23 (3.3) 47 (6.5) 296 (12.4) Λοιμωξη ανωτ. αναπνευστικου 32 (4.6) 75 (3.2) 77 (3.2) Υπερίδρωση 17 (2.5) 73 (3.1) 247 (10.3) Υπογλυκαιμία 4 (0.6) 58(2.5) 50 (7.0) 225 (9.4) Incidence of Adverse Events ≥5% in Combination Studies of Vildagliptin This slide presents pooled adverse-event data from combination studies of vildagliptin. Data are displayed for vildagliptin 50 mg once daily, 50 mg twice daily, placebo, and all active comparator treatments.1 The incidence of adverse events was generally low. Overall, the data show that vildagliptin combination therapy is generally well tolerated in patients with type 2 diabetes mellitus. Reference 1. Summary of Clinical Safety, 5 December 2007. Table 4–1c. Novartis Pharmaceuticals Preferred terms are sorted by descending order of incidence in the vildagliptin 50 mg twice-daily group. A patient with multiple adverse-event occurrences on one treatment is counted once in the adverse-event category for that treatment. Comp=comparator; PBO=placebo; vilda=vildagliptin Adapted from Summary of Clinical Safety, 5 December 2007. Tables 4-1c. Novartis Pharmaceuticals.

Incidence of Adverse Events >5% in Combination Studies of Vildagliptin Preferred term Vilda 50 mg once daily N=693 n (%) Vilda 50 mg twice daily N=2343 n (%) Total PBO N=718 n (%) Total comp N=2387 n (%) Any 411 (59.3) 1466 (62.6) 468 (65.2) 1611 (67.5) Nasopharyngitis 44 (6.3) 126 (5.4) 41 (5.7) 134 (5.6) Dizziness 33 (4.8) 125 (5.3) 43 (6.0) 207 (8.7) Headache 34 (4.9) 21 (2.9) 114 (4.8) Influenza 18 (2.6) 86 (3.7) 40 (5.6) 83 (3.5) Asthenia 22 (3.2) 85 (3.6) 28 (3.9) 146 (6.1) Tremor 23 (3.3) 47 (6.5) 296 (12.4) Upper respiratory tract infection 32 (4.6) 75 (3.2) 77 (3.2) Hyperhidrosis 17 (2.5) 73 (3.1) 247 (10.3) Hypoglycemia 4 (0.6) 58(2.5) 50 (7.0) 225 (9.4) Incidence of Adverse Events ≥5% in Combination Studies of Vildagliptin This slide presents pooled adverse-event data from combination studies of vildagliptin. Data are displayed for vildagliptin 50 mg once daily, 50 mg twice daily, placebo, and all active comparator treatments.1 The incidence of adverse events was generally low. Overall, the data show that vildagliptin combination therapy is generally well tolerated in patients with type 2 diabetes mellitus. Reference 1. Summary of Clinical Safety, 5 December 2007. Table 4–1c. Novartis Pharmaceuticals Preferred terms are sorted by descending order of incidence in the vildagliptin 50 mg twice-daily group. A patient with multiple adverse-event occurrences on one treatment is counted once in the adverse-event category for that treatment. Comp=comparator; PBO=placebo; vilda=vildagliptin Adapted from Summary of Clinical Safety, 5 December 2007. Tables 4-1c. Novartis Pharmaceuticals.

Any AE in Monotherapy Safety Population: Normal Renal Function vs Mild Renal Impairment Vilda 100 mg daily Placebo Active comparators 200 150 Incidence per 100 SYE * 100 50 Normal Renal Function Mild Renal Impairment Glomerular filtration rate (GFR)* (mL/min/1.73 m2) as follows: Normal: ≥90; Mild renal insufficiency: 60 to <90; Moderate renal insufficiency: 30 to <60; Severe renal insufficiency: <30 AE=adverse event; SYE=subject years of exposure; Vilda=vildagliptin. Thuren T, et al. Poster 881. Presented at: 43rd Annual Meeting of the European Association for the Study of Diabetes; September 17-21, 2007; Amsterdam, The Netherlands. 77

Αποτελεσματικότητα και ασφάλεια της ινκρετινοθεραπείας στον ΣΔ τύπου ΙΙ Μεταανάλυση 29 τυχαιοποιημένων – controlled μελετών (1966- 2007) Ασφάλεια: Oι DPP- 4 αναστολείς συνδέθηκαν με αυξημένο κίνδυνο λοιμώξεων (risk ratio 1,2 για ρινοφαρυγγίτιδα και 1,5 για λοιμώξεις ουροφόρων οδών) και κεφαλαλγίας (risk ratio 1,4) R. Amori, A. Pittas et al. JAMA 2007; 298: 194

Vildagliptin: Superior GI Tolerability Duration: 52 weeks Vilda vs met * Vilda 50 mg twice daily (n=511) Met 1000 mg twice daily (n=249) Vildagliptin: Superior GI Tolerability This 52-week, multicenter, randomized, double-blind study compared vildagliptin with metformin in drug-naïve patients with type 2 diabetes mellitus (T2DM).1 Drug-naïve patients (HbA1c 7.5–11.0%) were randomized to vildagliptin 50 mg twice daily or metformin 1000 mg twice daily. Twice as many metformin-treated patients experienced gastrointestinal (GI) adverse events compared with vildagliptin-treated patients (P <0.001). A greater proportion of metformin-treated patients than vildagliptin-treated patients experienced the component adverse events of abdominal pain, diarrhea, dyspepsia, flatulence, nausea, and vomiting. These findings illustrate that vildagliptin possesses a superior tolerability profile to metformin in respect of GI side effects, thus offering considerable clinical benefit to drug-naïve patients with T2DM. Reference Schweizer A, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med 2007; 24: 955-961. Any GI event Abdominal pain Constipation Diarrhea Dyspepsia Flatulence Nausea Vomiting GI=gastrointestinal; met=metformin; vilda=vildagliptin *P <0.001 (for GI-related events). Schweizer A, et al. Diabet Med 2007; 24: 955-961.

Galvus Labeling Recommendations Regarding Liver Monitoring LFTs should be performed prior to the initiation of treatment with Galvus. Galvus is not recommended in patients with a pre-treatment ALT or AST > 2.5X the upper limit of normal according to the BPI or above 3X according to European SmPC LFTs should be monitored during Galvus treatment at three-month intervals during the first year and periodically thereafter Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal Should an increase in AST or ALT of 3 X upper limit of normal or greater persist, withdrawal of therapy with Galvus is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Galvus and contact their physician immediately Following withdrawal of treatment with Galvus and LFT normalisation, vildagliptin treatment should not be reinitiated LFT = liver function test; AST = aspartate aminotransferase; ALT = alanine aminotransferase BPI = Basic prescribing information SmPC = European Summary of Product Characteristics (SmPC)

ΠΛΕΙΟΤΡΟΠΙΚΕΣ ΔΡΑΣΕΙΣ

Vildagliptin: Neutral Effect on Fasting Lipids (50 mg once daily) Pooled analysis at 24 weeks TG TC LDL-C HDL-C n= BL (mmol/L)= 181 2.2 181 5.1 168 3.0 180 1.2 NS * Change from BL (%) Vildagliptin: Neutral Effect on Fasting Lipids Data from four trials were pooled to assess the effect of vildagliptin 50 mg twice daily on lipid parameters in patients with type 2 diabetes mellitus (T2DM). All trials were double-blind, randomized, multicenter, parallel-group studies. Three trials lasted for 24 weeks; the fourth trial lasted for 52 weeks. The percentage change from baseline at 24 weeks in the following parameters was analyzed for 1271 patients who underwent lipid tests: 1) triglycerides (TG) 2) total cholesterol (TC) 3) low-density lipoprotein cholesterol (LDL-C) 4) high-density lipoprotein cholesterol (HDL-C) Pooled analysis of the 50 mg once-daily dose showed that there was a significant improvement from baseline in HDL-C (P <0.01); the +4.2% change in TG, +0.6% change in TC, and +1.0% change in LDL-C were not statistically significant. These data demonstrate that vildagliptin has a modest positive effect on the lipid profile in patients with T2DM. References Nathwani A. The use of vildagliptin for the treatment of patients with type 2 diabetes. Oral presentation at ADA Annual Meeting, Washington, DC, June 913, 2006. Summary of Clinical Efficacy, 17 December 2007. Tables 4-1b, 4-2b, 4-3-b, 4-4b. Novartis Pharmaceuticals. NS NS Vilda 50 mg once daily BL=baseline; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; NS=not significant; TC=total cholesterol; TG=triglycerides *P <0.01 from BL. Pooled analysis from LAF237A2301, 2309 (at 24 weeks), 2327, 2355; primary intention-to-treat population; n refers to patients with TG test. Nathwani A. Presented at ADA Annual Meeting, June 9–13, 2006; Washington, DC. Summary of Clinical Efficacy, 17 December 2007. Tables 4-1b, 4-2b, 4-3b, 4-4b. Novartis Pharmaceuticals.

Vildagliptin: Effect on Lipid Parameters Relative to Rosiglitazone TG TC LDL-C HDL-C 14 12 10 8 6 ** 4 Change from BL (%) 2 Vildagliptin: Effect on Lipid Parameters Relative to Rosiglitazone The effect of vildagliptin on various lipid parameters has been compared with that of rosiglitazone as part of a 24-week, multicenter, randomized, double-blind, parallel-group study of drug-naïve patients with type 2 diabetes mellitus who received vildagliptin 50 mg twice daily (n=459) or rosiglitazone 8 mg once daily (n=238).1 Relative to rosiglitazone, vildagliptin improved the lipid profile, producing significant decreases from baseline in triglycerides (−9%, P=0.010), total cholesterol (−14%, P <0.001), and low-density lipoprotein (−16%, P <0.001), but showed a smaller improvement in high-density lipoprotein-cholesterol (HDL-C) from baseline (+4% vs +9%, −5%, P=0.003 for between-group difference). Relative to rosiglitazone, vildagliptin also decreased the total-to-HDL-C ratio by 9.1% (P <0.0001). The ability of vildagliptin to improve glycemic control is similar to rosiglitazone at 24 weeks. However, vildagliptin is associated with improvements in several important lipid parameters. Reference 1. Rosenstock J, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. A 24-week, double-blind, randomized trial. Diabetes Care 2007; 30: 217-223. −2 * −4 ** ** Vilda 50 mg twice daily (n=449) Rosi 8 mg once daily (n=231) −6 −8 BL=baseline; HDL=high-density lipoprotein; LDL-C=low-density lipoprotein cholesterol; rosi=rosiglitazone; TC=total cholesterol; TG=triglycerides; vilda=vildagliptin. Primary intention-to-treat population; n refers to the patient number in the TG test. *P=0.01; **P <0.003 vs rosi. Rosenstock J, et al. Diabetes Care 2007; 20: 217-223.

Vildagliptin Improves Postprandial Lipid and Lipoprotein Metabolism Plasma TG Chylomicron TG 0.8 4.0 Before vilda, week 0 (n=13) 3.5 0.6 Vilda 50 mg twice daily, week 4 (n=15) 3.0 mmol/L 2.5 mmol/L 0.4 2.0 0.2 1.5 1.0 0.0 −1 1 2 3 4 5 6 7 8 −1 1 2 3 4 5 6 7 8 Time (h) Time (h) Chylomicron apo B-48 Chylomicron cholesterol 0.08 0.06 0.04 0.02 0.00 −1 1 2 3 4 5 6 7 8 Time (h) 0.50 0.40 0.30 0.20 0.10 0.00 −1 1 2 3 4 5 6 7 8 Time (h) Vildagliptin Improves Postprandial Lipid and Lipoprotein Metabolism This randomized, double-blind study assessed the effects of vildagliptin on postprandial lipid and lipoprotein metabolism in drug-naïve patients with type 2 diabetes mellitus.1 Patients received vildagliptin (50 mg twice daily; n=15) or placebo (n=16, not shown) for 4 weeks. Before and after the treatment period, total serum triglycerides (TG) were determined for 8 hours following a fat-rich mixed meal.1 Relative to placebo, 4 weeks of vildagliptin treatment significantly decreased the area under the curve (AUC)0-8h for total TG (P=0.037, data not shown).1 Four-week vildagliptin treatment resulted in a significant decrease in AUC0-8h for postprandial plasma TG, chylomicron TG, chylomicron apolipoprotein B-48, and chylomicron cholesterol after a fat-rich meal. Reference 1. Matikainen N, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 2006; 49: 2049-2057. mg/L mmol/L TG=triglycerides; vilda=vildagliptin Matikainen N, et al. Diabetologia 2006; 49: 2049-2057.

Vildagliptin: Favorable effects on BP observed Duration: 52 weeks Vilda vs met DBP SBP n= 89 53 150 84 BL= 94 94 149 150 Change from BL (mmHg) Vildagliptin: Mean Change in BP in T2DM Patients with SBP ≥140 mmHg and DBP ≥90 mmHg This 52-week, multicenter, randomized, double-blind study compared vildagliptin 50 mg twice daily (n=526) or metformin 1000 mg twice daily (n=254) in drug-naïve patients with type 2 diabetes mellitus (HbA1c 7.5–11.0%).1 Significant decreases from baseline in patients with high blood pressure were observed.2 The mean systolic blood pressure (SBP) decrease for vildagliptin-treated patients compared with metformin-treated patients at 1 year was −9.1 vs −5.3 mmHg, respectively (P <0.05 vs metformin). The mean diastolic blood pressure (DBP) decrease was −7.5 vs −4.2 mmHg (P <0.05 vs metformin), respectively. This study shows that in patients with high baseline blood pressure measurements, vildagliptin is associated with decreases in both SBP and DBP, which were significantly greater than those obtained with metformin. These preliminary observations need further investigation. References 1. Schweizer A, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes. Diabet Med 2007; 24: 955-961. 2. Bosi E, et al. Poster presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P. * * Met 1000 mg twice daily Vilda 50 mg twice daily BL=baseline; BP=blood pressure; DBP=diastolic blood pressure; met=metformin; SBP=systolic blood pressure; T2DM=type 2 diabetes; vilda=vildagliptin *P <0.05 vs met. Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.

Overall Incidence of Serious Cardiovascular Events by Treatment Safety population up to 24 weeks of treatment Odds Ratio Serious CV events n/N (%) Vildagliptin 50 mg once daily Vildagliptin 50 mg twice daily Vilda 50 mg qd* 08/1469 (0.54) 0.79 Vilda 50 mg bid* 25/4594 (0.54) 0.79 Placebo 09/1304 (0.69) Vilda 50 mg qd** 08/1469 (0.54) 0.70 Vilda 50 mg bid** 25/4594 (0.54) 0.70 All comparators 34/4357 (0.78) Overall Incidence of Serious Cardiovascular Events by Treatment This pooled safety analysis included data up to 24 weeks from 19 studies: 11 monotherapy and eight combination therapy (with metformin, thiazolidinediones, or sulfonylureas).1 The mean age of patients was 55.6 years for those receiving vildagliptin 50 mg once daily, 55.3 years for those receiving vildagliptin 50 mg twice daily, 56.4 years for those receiving placebo, and 55.9 years for those receiving comparators. The overall incidence of cardiovascular serious adverse events for vildagliptin 50 mg once daily and 50 mg twice daily was lower when compared with placebo or all comparators combined (0.54% and 0.54% vs 0.69% or 0.78%, respectively). These data from ~6000 vildagliptin-treated patients provide reassurance with respect to the cardiovascular profile of vildagliptin. Reference Kothny W, et al. Poster 915. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes; September 7–11, 2008; Rome, Italy. 0.01 0.1 1 10 100 Vildagliptin better Vildagliptin worse *Comparison vs placebo; **Comparison vs all comparators. bid=twice daily; comparators=all non-vildagliptin treatment groups; CV=cardiovascular; qd=once daily; vilda=vildagliptin Kothny W, et al. Poster 915. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes; September 7-11, 2008; Rome, Italy. 86

Η ΘΕΣΗ ΤΗΣ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗΣ ΣΤΗΝ ΑΝΤΙΔΙΑΒΗΤΙΚΗ ΑΓΩΓΗ

Η αποτελεσματικότητα στην μείωση και διατήρηση των επιπέδων της HbA1c Αξιολόγηση δράσης αξιοπιστίας και χρησιμότητας των αντιδιαβητικών αγωγών ΒΙΛΝΤΑΓΛΙΠΤΙΝΗ Η αποτελεσματικότητα στην μείωση και διατήρηση των επιπέδων της HbA1c Η ασφάλεια του φαρμάκου Η αποδοχή και ευκολία χρήσης από τον ασθενή Άλλα χαρακτηριστικά δράσης στο σωματικό βάρος στο καρδιαγγειακό κίνδυνο Το (οικονομικό) κόστος της αγωγής V V V V ? _ Nathan D NEJM 2007

Αντιδιαβητική αγωγή Υγιεινοδιαιτητική παρέμβαση (Διατροφή – μείωση βάρους – σωματική δραστηριότητα) Metformin (γλυκαιμική ρύθμιση, μειωμένα CV συμβάματα – όχι υπογλυκαιμίες – όχι αύξηση βάρους) A1c>7% Προσθήκη δεύτερου φαρμάκου Sulfonylurea Glinides TZDs DPP-4 Αναστολείς Exenatide Ινσουλίνη Φθηνή αγωγή Ταχείας δράσης Όχι υπογλυκαιμίες Εργάζεται πάντα Υπογλυκαιμίες Ακριβή αγωγή Όχι σωματικού βάρους Οχι ακριβη αγωγη Λειτουργία β-κυττάρου (;) Καρδιαγγειακή ασφάλεια (;) Μικρή εμπειρία Ναυτία, Ακριβή αγωγή Σωματικού βάρους Nauck 2008

Αλγόριθμος αντιδιαβητικής αγωγής Consensus Statement ADA και EASD 2008 Αλγόριθμος 1: Παραδοσιακές αγωγές (καλά τεκμηριωμένες) Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Intensive Insulin Στη διάγνωση: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea 1ο Βήμα 2ο Βήμα 3ο Βήμα Αλγόριθμος 2: Νέες αγωγές (Λιγωτερο καλα τεκμηριωμενες) Lifestyle + Metformin + Pioglitazone Όχι υπογλυκαιμία Οίδημα/Καρδ. Ανεπάρκεια Απώλεια οστικής μάζας Lifestyle + Metformin + Pioglitazone + Sulfonylurea* Lifestyle + Metformin + GLP-1 αγωνιστής Όχι υπογλυκαιμία Απώλεια βάρους Ναυτία/εμετός Lifestyle + Metformin + Basal insulin Nathan et al, Diabetologia, on line 2008, DOI. 10.1007/s00125-008-1157-y

ADA and EASD algorithm for the management of type 2 diabetes Tier 1: Well validated therapies At diagnosis: Lifestyle + met Lifestyle and met + basal insulin Lifestyle and met + intensive insulin Lifestyle and met + SUa Step 1 Step 2 Step 3 Tier 2: Less well validated therapies Lifestyle and met + pio Lifestyle and met + pio + SUa No hypoglycaemia Oedema/CHF Bone loss ADA-EASD Consensus Algorithm for T2DM The ADA/EASD algorithm’s goal is to achieve and maintain HbA1c levels of <7%. The well-validated core therapies represent the preferred route. Tier 1: well-validated therapies Step 1: lifestyle intervention and metformin Lifestyle interventions remain an underlying theme for the management of type 2 diabetes mellitus; however as most individuals fail to achieve goals with lifestyle intervention alone, metformin should be initiated concurrently at diagnosis. Step 2: additional medications If lifestyle intervention and maximal tolerated doses of metformin fail to sustain goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1C goal is not achieved. The consensus is to choose either insulin or a sulfonylurea (SU). Step 3: further adjustments If lifestyle, metformin, and a basal insulin or SU do not result in glycaemic control, start or intensify insulin therapy: insulin secretagogues (SUs or glinides) should be discontinued, or tapered and then discontinued, since they are not considered synergistic with insulin. Tier 2: less-well validated therapies In selected clinical settings, the second tier algorithm may be considered. When hypoglycaemia is particularly undesirable, the addition of exenatide or pioglitazone may be considered (rosiglitazone is not recommended). If weight loss is a major issue and HbA1c is close to target (<8.0%), exenatide is an option. If these interventions are not effective in achieving target HbA1c, or are not tolerated, addition of an SU could be considered. Alternatively, tier 2 interventions should be stopped and basal insulin started. Reference Nathan et al. Management of Hyperglycemia in Type 2 Diabetes Mellitus: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 2008 [Epub]. Lifestyle and met + GLP-1 agonistb Lifestyle and met + basal insulin No hypoglycaemia Weight loss Nausea/vomiting Reinforce lifestyle interventions every visit and check HbA1C every 3 months until HbA1C is <7% and then at least every 6 months. The interventions should be changed if HbA1C is ≥7% aSUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. Met=metformin; Pio=pioglitazone; SU=sulfonylurea Nathan et al., Diabetes Care 2008 [Epub]

EASD/ADA 2006 Consensus Γιατί η μετφορμίνη φαρμακο πρώτης επιλογής; Μειώνει την HbA1c 1,5-2% Δεν αυξάνει το σωματικό βάρος και δεν προκαλεί υπογλυκαιμία Έχει λίγες παρενέργειες Μειώνει τους θανάτους από ΕΜ (UKPDS) Έχει χαμηλό κόστος

Θεραπεία με σουλφονυλουρίες Πλεονεκτήματα Αποτελεσματικότητα Προάγουν την ενδογενή παραγωγή ινσουλίνης Μειονεκτήματα Πιθανός κίνδυνος σοβαρής υπογλυκαιμίας1 Αύξηση υπερινσουλιναιμίας και σωματικού βάρους1 Μακροπρόθεσμη αποτυχία  30% των ασθενών / έτος 2,3 Δεν βελτιώνουν την ευαισθησία στην ινσουλίνη 4 Αυξημένες δόσεις, μπορεί να συνδέονται με αυξημένη καρδιαγγειακή θνησιμότητα ;;; 5. Οι α΄γενεάς μπορούν να προκαλέσουν αρρυθμία. Απώλεια του γλυκαμικού ελέγχου μακροχρόνια 5,6 1 Krentz. Drug Safety 1994; 11: 234-238, 2 Pontiroli A. Diabetes/Metabolism Reviews 1994; 10(1): 31-43, 3 Sulphonylureas. In: Martindale The Extra Pharmacopoeia. 31st Edition,1996; Royal Pharmaceutical Society, 4 UKPDS 16: Diabetes 1995; 44: 1249-1258. 5 National Diabetes Centre (www.diabetes-mellitus.org/sfuwarning) 6 UKPDS 34: Lancet 1998; 352: 854-865

Συνδυασμός SU + Μετφορμίνης: RR σε σύγκριση με SU ή Μετφορμίνη για ΚΑ θνησιμότητα & νοσηλεία Rao AD et al. Diabetes Care 31:1672–1678, 2008

Combination of SUs and Metformin may be Linked to Higher Risk for CVD and All-cause Mortality* Meta-analysis data from 9 clinical studies Risk ratios for composite end point of CVD hospitalizations or CVD mortality* Source study reference Relative risk (95% CI) Combination therapy Control group Bruno (1999) Olsson (2000) Johnson (2005) Koro (2005) Evans (2006a) Evans (2006b) Evans (2006c) Overall 1.04 1.86 0.96 1.38 2.24 1.52 1.43 (0.62, 1.75) (1.33, 2.61) (0.82, 1.12) (1.13, 1.69) (1.26, 3.99) (1.03, 3.35) (0.84, 2.76) (1.10, 1.85) NS 264/1081 133/1252 92/985 12/113 NS 541/2138 229/2286 Combination of SUs and Metformin may be Linked to Higher Risk for CVD and All-cause Mortality The authors conducted a meta-analysis to evaluate the risk for all-cause mortality and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients taking a combination of a sulfonylurea (SU) and metformin.1 Nine reports were included in this analysis following an extensive MEDLINE search (January 1966-July 2007). The selected studies included the assessment of CVD risk and mortality including the relative risk or hazard ratio, for combination of SU and metformin. This meta-analysis reported that the risk ratios (95% confidence interval) for T2DM patients taking SU and metformin combination were the following: for all-cause mortality 1.19 (0.88-1.62); for CVD mortality 1.29 (0.73-2.27); for a composite end point of CVD hospitalizations and mortality 1.43 (1.10-1.85) – presented on the slide The combination of SU and metformin did not show a significantly increased risk for CVD mortality or all-cause mortality alone. However, the risk ratio of the composite end point of CVD hospitalization or mortality was significantly increased, irrespective of the comparator group. The authors present several possible explanations for such an observation, one of which is the tendency of SUs to cause hypoglycemia which may be further aggravated by the metformin-caused decrease of hepatic glucose production, possibly impairing the recovery from hypoglycemia. Hypoglycemia may be linked to the risk for CVD abnormalities, eg ischemia. Larger-scale studies will have to be carried out to further characterize these results. Reference Rao A, et al. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality? Diabetes Care. 2008; 31: 1672–1678. 0.25 1.00 4.00 SU combo with met better than comparators SU combo with met worse than comparators CI=confidence interval; CVD=cardiovascular disease; met=metformin; NS=not specified; SU=sulfonylureas *Composite end point of CVD hospitalizations or CVD mortality – only statistically significantly increased end point. Rao A, et al. Diabetes Care. 2008; 31: 1672–1678.

Αντιδιαβητική αγωγή Υγιεινοδιαιτητική παρέμβαση (Διατροφή – μείωση βάρους – σωματική δραστηριότητα) Metformin (γλυκαιμική ρύθμιση, μειωμένα CV συμβάματα – όχι υπογλυκαιμίες – όχι αύξηση βάρους) A1c>7% Προσθήκη δεύτερου φαρμάκου Sulfonylurea Glinides TZDs DPP-4 Αναστολείς Exenatide Ινσουλίνη Φθηνή αγωγή Ταχείας δράσης Όχι υπογλυκαιμίες Εργάζεται πάντα Υπογλυκαιμίες Ακριβή αγωγή Όχι σωματικού βάρους Οχι ακριβη αγωγη Λειτουργία β-κυττάρου (;) Καρδιαγγειακή ασφάλεια (;) Μικρή εμπειρία Ναυτία, Ακριβή αγωγή Σωματικού βάρους Nauck 2008

Ανεπιθύμητες ενέργειες TZDs Ήπαρ • Παρακολούθηση των τρανσαμινασών πριν από την έναρξη, ανά δίμηνο το πρώτο έτος και αργότερα στη συνέχεια. Διακοπή αν οι τιμές > 3πλάσιο. Οίδημα 6% σημαντική κατακράτηση ύδατος και εμφάνιση οιδήματος. Αύξηση σωματικού βάρους 3-4 kg. Οφείλεται σε συνδυασμό κατακράτησης ύδατος και αύξηση του λιπώδους ιστού Αναιμία Μικρή μείωση του αιματοκρίτου Κατάγματα οστών Άλλες Κεφαλαλγία, αϋπνία, ζάλη, μετεωρισμός. Οίδημα οπτικής θηλής ˜ ˜

PROactive: Επίπτωση του οιδήματος και μέγεθος πρόσληψης βάρους % οιδήματος χωρίς HF Πρόσληψη βάρους (kg) P <0,0001 PROactive: Επίπτωση οιδήματος και μέγεθος πρόσληψης βάρους Ο σκοπός της PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) ήταν να εξακριβώσει αν η πιογλιταζόνη ελάττωσε τη νοσηρότητα και τη θνησιμότητα από μακροαγγειακά αίτια σε ασθενείς υψηλού κινδύνου με σακχαρώδη διαβήτη τύπου 2 (T2DM). Η PROactive ήταν προοπτική, τυχαιοποιημένη, ελεγχόμενη μελέτη σε 5238 ασθενείς με T2DM που είχαν ενδείξεις μακροαγγειακής νόσου. Οι ασθενείς κατανεμήθηκαν σε ομάδες ώστε να λαμβάνουν πιογλιταζόνη από το στόμα, που τιτλοποιήθηκε από 15 mg έως 45 mg (n=2605), ή ανάλογο εικονικό φάρμακο (n=2633), επιπροσθέτως των φαρμάκων ελάττωσης της γλυκόζης και των άλλων φαρμάκων που ελάμβαναν ήδη.1 Το κύριο καταληκτικό σημείο ήταν η σύνθεση της θνησιμότητας από όλα τα αίτια, του μη θανατηφόρου εμφράγματος του μυοκαρδίου (συμπεριλαμβανομένου του σιωπηλού εμφράγματος του μυοκαρδίου), του αγγειακού εγκεφαλικού επεισοδίου, του οξέος στεφανιαίου συνδρόμου, της ενδαγγειακής ή χειρουργικής επέμβασης στις στεφανιαίες αρτηρίες ή στις αρτηρίες του κάτω άκρου και του ακρωτηριασμού άνω του αστραγάλου. Σε κάθε επίσκεψη λαμβανόταν δεδομένα για τις ανεπιθύμητες ενέργειες. Ο μέσος χρόνος παρακολούθησης στη μελέτη ήταν 34,5 μήνες. Αν και το 7% (149 από 2065) και το 4% (108 από 2633) όσων ήταν στην ομάδα της πιογλιταζόνης και του εικονικού φαρμάκου, αντίστοιχα, εισήχθησαν στο νοσοκομείο με καρδιακή ανεπάρκεια, τα ποσοστά θνησιμότητας από καρδιακή ανεπάρκεια δεν διέφεραν μεταξύ των ομάδων και οι συγγραφείς κατέληξαν στο συμπέρασμα ότι η πιογλιταζόνη ελάττωσε τη σύνθεση της θνησιμότητας από όλα τα αίτια, του μη θανατηφόρου εμφράγματος του μυοκαρδίου και του αγγειακού εγκεφαλικού επεισοδίου σε αυτούς τους ασθενείς. Ωστόσο, 562 ασθενείς (21,6%) στην ομάδα της πιογλιταζόνης ανέπτυξαν οίδημα χωρίς καρδιακή ανεπάρκεια (συμβατό με το προφίλ ανεπιθύμητων ενεργειών της πιογλιταζόνης), σε σύγκριση με 341 (13%) στην ομάδα του εικονικού φαρμάκου. Επιπλέον, παρατηρήθηκε αύξηση 3,6 kg στο μέσο σωματικό βάρος στην ομάδα της πιογλιταζόνης έναντι ελάττωσης κατά 0,4 kg στην ομάδα του εικονικού φαρμάκου.1 Βιβλιογραφία 1. Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366: 12791289. Εικονικό φάρμακο πιογλιταζόνη 45 mg την ημέρα HF=καρδιακή ανεπάρκεια Προσαρμογή από Dormandy JA, et al. Lancet 2005; 366: 1279–1289.

Η χρήση TZD σχετίζεται με αυξημένη επίπτωση συμφορητικής καρδιακής ανεπάρκειας Μελέτη DREAM Μελέτη PROactive 20 P=0,01 15 P <0,0001 14 15 11 Αριθμός επεισοδίων CHF 10 10 8 % Ασθενών με HF 5 5 Η χρήση TZD σχετίζεται με αυξημένη επίπτωση καρδιακής συμφορητικής ανεπάρκειας Τα αποτελέσματα από την DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) και την PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) κατέδειξαν συμφορητική καρδιακή ανεπάρκεια που σχετίζεται με τις θειαζολιδινεδιόνες (TZD).1,2 Σκοπός της DREAM ήταν να αξιολογήσει προοπτικά την ικανότητα της ροσιγλιταζόνη να προλάβει το σακχαρώδη διαβήτη τύπου 2 (T2DM) σε άτομα με υψηλό κίνδυνο ανάπτυξης αυτής της πάθησης. Ασθενείς (n=5269) με διαταραγμένη γλυκόζη νηστείας και/ή διαταραγμένη ανοχή γλυκόζης χωρίς προηγούμενη καρδιαγγειακή νόσο τυχαιοποιήθηκαν σε ροσιγλιταζόνη (8 mg την ημέρα n=2365) ή εικονικό φάρμακο (n=2634) και παρακολουθήθηκαν κατά μέσο όρο για 3 έτη.1 Αν και τα ποσοστά των καρδιαγγειακών επεισοδίων ήταν παρόμοια στις δύο ομάδες, 14 (0,5%) συμμετέχοντες στην ομάδα της ροσιγλιταζόνης και 2 (0,1%) στην ομάδα του εικονικού φαρμάκου ανέπτυξαν καρδιακή ανεπάρκεια (P=0,01).1 Σκοπός της PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) ήταν να αξιολογήσει προοπτικά αν η πιογλιταζόνη ελαττώνει τη νοσηρότητα και τη θνησιμότητα από μακροαγγειακά αίτια σε ασθενείς με T2DM που είχαν ενδείξεις μακροαγγειακής νόσου. Οι ασθενείς (n=5238) τυχαιοποιήθηκαν σε πιογλιταζόνη 15 mg έως 45 mg (n=2605) ή ανάλογο εικονικό φάρμακο (n=2633), που χορηγήθηκαν επιπροσθέτως των φαρμάκων ελάττωσης της γλυκόζης και των άλλων φαρμάκων που ελάμβαναν ήδη. Ο μέσος χρόνος παρατήρησης στη μελέτη ήταν 34,5 μήνες.2 Αν και τα ποσοστά θνησιμότητας από καρδιακή ανεπάρκεια δεν διέφεραν μεταξύ των ομάδων (P=0,634), υπήρχαν αναφορές καρδιακής ανεπάρκειας σε 281 ασθενείς (11%) στην ομάδα της πιογλιταζόνης σε σύγκριση με 198 ασθενείς (8%) στην ομάδα του εικονικού φαρμάκου (P <0,0001).2 Βιβλιογραφία DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006; 368: 10961105. Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366: 12791289. 2 Ροσιγλιταζόνη Πιογλιταζόνη ≤45 mg την ημέρα Εικονικό φάρμακο Εικονικό φάρμακο CHF=συμφορητική καρδιακή ανεπάρκεια Προσαρμογή από DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105. HF=καρδιακή ανεπάρκεια Προσαρμογή από Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.

ADOPT: Αυξημένα κατάγματα άκρων σε γυναίκες που ελάμβαναν ροσιγλιταζόνη Ροσιγλιταζόνη (n=1456) Γλυβουρίδη (n=1441) Μετφορμίνη (n=1454) * Ασθενείς (%) * ** ** * ADOPT: Αυξημένα κατάγματα άκρων σε γυναίκες που ελάμβαναν ροσιγλιταζόνη Η μελέτη ADOPT (A Diabetes Outcome Progression Trial) ήταν μία διπλή-τυφλή, τυχαιοποιημένη, ελεγχόμενη μελέτη που σχεδιάστηκε να διερευνήσει την αποτελεσματικότητα της ροσιγλιταζόνης, σε σύγκριση με άλλα από του στόματος φάρμακα που ελαττώνουν τη γλυκόζη, όσον αφορά τη διατήρηση του μακροχρόνιου γλυκαιμικού ελέγχου σε ασθενείς με πρόσφατα διαγνωσμένο σακχαρώδη διαβήτη τύπου 2 (T2DM).1 Η ροσιγλιταζόνη, η μετφορμίνη, και η γλυβουρίδη αξιολογήθηκαν ως αρχική θεραπεία σε ασθενείς (n=4360) που αντιμετωπίστηκαν κατά μέσο όρο επί 4 έτη. Η 5ετής αθροιστική επίπτωση της αποτυχίας της μονοθεραπείας (που ορίζεται ως γλυκόζη πλάσματος νηστείας >180 mg/dL) ήταν 15% για τη ροσιγλιταζόνη σε σύγκριση με 21% για τη μετφορμίνη και 34% για τη γλυβουρίδη (P <0,001 και για τις δύο συγκρίσεις ). Από την εξέταση των δεδομένων των ανεπιθύμητων ενεργειών διαπιστώθηκε μεγαλύτερος κίνδυνος καταγμάτων σε γυναίκες ασθενείς που λάμβαναν ροσιγλιταζόνη απ’ότι σε αυτές που ελάμβαναν μετφορμίνη ή γλυβουρίδη. Τόσο τα κατάγματα των άνω άκρων όσο και τα κατάγματα των κάτω άκρων ήταν πιο συχνά στην ομάδα της ροσιγλιταζόνης, ενώ το συνολικό ποσοστό καταγμάτων για τη ροσιγλιταζόνη ήταν σημαντικά υψηλότερο απ’ότι για οποιονδήποτε από τους άλλους παράγοντες.1 Επιπλέον, παρατηρήθηκαν και άλλες ανεπιθύμητες ενέργειες συμπεριλαμβανομένης της πρόσληψης βάρους, του οιδήματος της αυξημένης χρήσης στατινών, της αυξημένης χρήσης θεραπείας για τη μείωση των λιπιδίων1 Βιβλιογραφία 1. Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355: 24272443. *P <0,01; **P <0,05 έναντι ροζιγλιταζόνης (μη τροποποιημένο, έλεγχος ενδεχομένων 2) Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.

META-ANALYSIS  καταγμάτων κατά 223% CMAJ 2009;180:32-9

CMAJ 2009;180:32-9

Managing of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy Μείωση Πλεονεκτήματα Μειονεκτήματα της HβΑ1c% Γλιταζόνες 0.5-1.4% Βελτίωση του Κατακράτηση υγρών λιπιδαιμικού προφίλ  χ 2 επίπτωση ΚΑ  ΟΕΜ++?, OEM+? Αύξηση βάρους Υψηλό κόστος + Η ΠΙΟΓΛΙΤΑΖΟΝΗ ++ Η ΡΟΣΙΓΛΙΤΑΖΟΝΗ Consensus statement update: Diabetologia 2008;51:8-11

Συγκριτική αξιολόγηση αντιδιαβητικών αγωγών 2ου βήματος Συγκριτική αξιολόγηση αντιδιαβητικών αγωγών 2ου βήματος Σουλφονυλουριες Γλιπτινες και Ινκρετινομιμητικα TZDs Επίδραση στο: Γλυκαιμική δράση ++ + Διατήρηση γλυκ. δρασης - +(?) ± Μεταγευματική υπεργλυκαιμία +++ Βελτίωση λειτουργίας β-κυττ. Υπογλυκαιμία Σωματικό βάρος 0 ή ↓ Καρδιαγγειακή επίδραση ? (?)

American Association of Clinical Endocrinologists: algorithm for patients with T2DM New slide Drug-naïve patients HbA1c 6%–7% Initiate monotherapy Metformin, TZD, secretagogues, DPP-4 inhibitors, α-glucosidase inhibitors HbA1c 7%–8% Initiate combination therapy Secretagogue + metformin, TZD, or α-glucosidase inhibitor TZD + metformin DPP-4 + metformin or TZD Secretagogue + metformin + TZD Fixed-dose combinations Insulin Lifestyle Changes HbA1c 8%–10% Intensify combination therapy To address fasting and postprandial glucose levels AACE Algorithm for Patients with T2DM All appropriate components of care (eg, medical nutrition therapy, weight management) should be aggressively implemented at the time of diagnosis. Patients should be persistently monitored and therapy titrated over 2 to 3 months until all American College of Endocrinology/American Association of Clinical Endocrinologists (ACE/AACE) glycemic goals are achieved. If glycemic goals are not achieved, more intensive regimens should be initiated. Patients currently treated with monotherapy or combination therapy who have not achieved glycemic goals will require either increased dosages of their current medications or the addition of a second or third medication. In patients with HbA1c >8%, symptomatic hyperglycemia, elevated fasting blood glucose levels, or exaggerated postprandial glucose excursions (regardless of HbA1c levels), insulin should be considered. Rapid-acting insulin analogs or premixed insulin analogs may be used in special situations. Inhaled insulin may be used as monotherapy or in combination with oral agents and long-acting insulin analogs. Insulin-oral medications: all oral medications may be used in combination with insulin; therapy combinations should be selected based on the patient’s self-monitoring of blood glucose profiles. Insulin therapy should be initiated to control hyperglycemia and to reverse glucose toxicity when the HbA1c level is >10%; insulin treatment (rapid-acting insulin analogs or inhaled insulin with long-acting insulin analogs or NPH, or premixed insulin analogs) can then be modified or discontinued once glucose toxicity is reversed. Exenatide may be combined with oral therapy where glycemic goals are not achieved. Insulin should be added in patients on maximum combination therapy (oral-oral, oral-exenatide) whose HbA1c levels are 6.5%–8.5%; where HbA1c levels are >8.5%, basal-bolus insulin therapy should be considered. Reference AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. AACE diabetes mellitus guidelines. Glycemic management. Endocr Pract 2007;13(Suppl 1):16-34. HbA1c >10% Initiate / intensify insulin therapy Patients currently pharmacologically treated As above Exenatide may be combined with oral therapies in patients not achieving goals DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007; 13 (Suppl 1): 16–34.

ΤΑ ΒΗΜΑΤΑ ΤΗΣ ΑΝΤΙΔΙΑΒΗΤΙΚΗΣ ΑΓΩΓΗΣ ΠΑΡΕΜΒΑΣΗ ΑΝΑΜΕΝΟΜΕΝΗ ΜΕΙΩΣΗ HbA1c% ΜΕ ΜΟΝΟΘΕΡΑΠΕΙΑ ΠΛΕΟΝΕΚΤΗΜΑΤΑ ΜΕΙΟΝΕΚΤΗΜΑΤΑ Tier 1: Καλά επικυρωμένη αγωγή Step 1: Αρχική αγωγή Lifestyle. Μείωση βάρους και σωματικής δραστηριότητας 1-2 Ευρέα οφέλη Αποτυχία για περισσότερους τον 1ο χρόνο Metformin 1,0-2,0 Μείωση βάρους Γαστρ/κές διαταραχές, αντενδεικνύεται επί νεφρικής ανεπάρκειας Step 2: επιπρόσθετη αγωγή Insulin 1.5-3.5 Ταχέως δραστικά, βελτιωμένο λιπιδ. προφίλ 1-4 ενέσεις ημερησίως, παρακολούθηση, βάρους, υπογλυκαιμίες, τα ανάλογα είναι ακριβά Sulfonylurea 1,0-2.0 Ταχέως δραστικά  Βάρους, υπογλυκαιμίες, (ιδίως με glibeniclamide ή chlorpropamide) Tier 2: όχι καλά επικυρωμένη αγωγή Thiazolidinedione 0,5-1,4% Βελτιωμένο λιπιδ. Profile (pioglitaz.) πιθανή μείωση Ε.Μ (pioglitaz.) Κατακράτηση υγρών, CHF,  βάρους, κατάγματα οστών, ακριβή αγωγή, ενδεχόμενη αύξηση ΜΙ (rosiglitaz.) GLP-1 αγωνιστές 0,5-1,0 Απώλεια βάρους 2 ενέσεις ημερησίως, συχνές γαστ/κές παρενέργειες, όχι τεκμηριωμένη η ασφάλεια μακράς διάρκειας, ακριβή αγωγή Άλλα φάρμακα Αναστολείς α- γλυκοζιδασών 0,5-0,8 Ουδέτερη επίδραση στο βάρος Γαστ/κές διαταραχές. 3 φορές/ ημ, ακριβή Glinide 0.5-1.5 Ταχέως δραστική  βάρους, 3 φορές/ημ, υπογλυκαιμίες, ακριβή αγωγή Αναστολείς DPP-IV Όχι τεκμηριωμένη η ασφάλεια μακράς διάρκειας, ακριβά D. M. Nathan et al, Diabetologia DOI 10.1007/s00125-008-1157-y

DPP-4 inhibitors are not included in the two tiers of preferred agents in this algorithm, owing their lower equivalent overall glucose-lowering effectiveness compared with the first and second tier agents and/or to their limited clinical data or relative expanse. The potential for this class of compounds to interfere with immune function is of concern; an increase in upper respiratory infections has been reported D. M. Nathan et al, Diabetologia DOI 10.1007/s00125-008-1157-y

Αντιδιαβητική αγωγή Υγιεινοδιαιτητική παρέμβαση (Διατροφή – μείωση βάρους – σωματική δραστηριότητα) Metformin (γλυκαιμική ρύθμιση, μειωμένα CV συμβάματα – όχι υπογλυκαιμίες – όχι αύξηση βάρους) A1c>7% Προσθήκη δεύτερου φαρμάκου Sulfonylurea Glinides TZDs DPP-4 Αναστολείς Exenatide Ινσουλίνη Φθηνή αγωγή Ταχείας δράσης Όχι υπογλυκαιμίες Εργάζεται πάντα Υπογλυκαιμίες Ακριβή αγωγή Όχι σωματικού βάρους Οχι ακριβη αγωγη Λειτουργία β-κυττάρου (;) Καρδιαγγειακή ασφάλεια (;) Μικρή εμπειρία Ναυτία, Ακριβή αγωγή Σωματικού βάρους Nauck 2008

Πότε χορηγούμε Vildagliptin Η προϋπόθεση ύπαρξης λειτουργικής ικανότητας του β – κυττάρου καθιστά την χορήγηση του φαρμάκου πλέον αποτελεσματική από την αρχική φάση εξέλιξης του διαβήτη

ΒΙΛΝΤΑΓΛΙΠΤΙΝΗ: Ως μονοθεραπεία ή σε συνδυασμό με μετφορμίνη ή γλιταζόνη ή σουλφονυλουρία Δοσολογία: 50 mg Χ 2 με ή χωρίς τροφή + ΜΕΤ ή TZD 50 mg X 1 + SU OXI σε μέτρια ή σοβαρή νεφρική δυσλειτουργία ΟΧΙ σε ηπατική δυσλειτουργία ή σε AST/ALT>3x Παρακολούθηση AST/ALT ανά 3μηνο τον 1ο χρόνο

ΒΙΛΝΤΑΓΛΙΠΤΙΝΗ + ΜΕΤΦΟΡΜΙΝΗ Δισκία των 50/850 mg ή των 50/1000 mg 2 φορές/ημέρα με το φαγητό

ΣΥΜΠΕΡΑΣΜΑΤΑ ΒΙΛΝΤΑΓΛΙΠΤΙΝΗ: χρήσιμο και ασφαλές φάρμακο + μετφορμίνη/έγκαιρη χορήγηση ΟΧΙ ΥΠΟΓΛΥΚΑΙΜΙΑ /ΑΥΞΗΣΗ ΣΩΜΑΤΙΚΟΥ ΒΑΡΟΥΣ

Νέα στρατηγική προσέγγιση στην αντιμετώπιση του ΣΔτ2 2008 1. Στοχεύοντας στην διόρθωση των παθοφυσιολογικών διαταραχών α) Αντίσταση στην ινσουλίνη : Μετφορμίνη- Γλιταζόνες β) Προστασία β- κυττάρου : Γλιταζόνες- Γλυπτινες γ) α- κύτταρο: Γλυπτινες Αλλαγή Στρατηγικής α) Επιθετική - Γρήγορη (3 μήνες), τροποποίηση αγωγής, με στόχο HbA1-c <7% (6,5%) β) Έγκαιρα- Συνδυασμοί : Δίαιτα- Άσκηση και Μετφορμίνη+ Γλιταζόνες ή Γλυπτινες Μετφορμίνη+ Σουλφονυλουρία(?) Έγκαιρη ινσουλινοθεραπεία Πολυπαραγοντικη αντιμετωπιση

ΠΕΡΙΣΤΑΤΙΚΑ ΑΣΘΕΝΩΝ ΑΠΟ ΤΟ ΙΑΤΡΕΙΟ ΛΙΠΙΔΙΩΝ

ΠΕΡΙΓΡΑΦΗ 1ης ΠΕΡΙΠΤΩΣΗΣ ΠΕΡΙΓΡΑΦΗ 1ης ΠΕΡΙΠΤΩΣΗΣ Γυναίκα 55 ετών με πρόσφατης έναρξης διαβήτη. FBG = 140 mg/dL, HbA1c = 7,4%, BMI = 32 Kg/m2. Ιστορικό υπέρτασης και οστεοπόρωσης. Η ασθενής δεν μπορεί να ανεχθεί τη θεραπεία με μετφορμίνη εξαιτίας γαστρεντερικών διαταραχών (διάρροιες)

ΕΝΑΛΛΑΚΤΙΚΗ ΘΕΡΑΠΕΙΑ?? Α. Γλιμεπιρίδη 2 mg/ημέρα Δ. Βασική ινσουλίνη 8 U/βράδυ s.c Ε. Εξενατίδη 10 μg Χ 2 s.c

ΣΟΥΛΦΟΝΥΛΟΥΡΙΑ ΥΠΕΡ: Γρήγορη ρύθμιση της γλυκόζης ΚΑΤΑ: Υπογλυκαιμίες Αύξηση ΣΒ Γρήγορη εξάντληση του β-κυττάρου

ΓΛΙΤΑΖΟΝΗ ΥΠΕΡ: Όχι υπογλυκαιμία Διατήρηση του β-κυττάρου ΚΑΤΑ: Αύξηση ΣΒ Αυξημένος κίνδυνος καταγμάτων

ΓΛΙΠΤΙΝΗ ΥΠΕΡ: Όχι υπογλυκαιμία Διατήρηση του β-κυττάρου Όχι αύξηση ΣΒ ΚΑΤΑ: ??

ΙΝΣΟΥΛΙΝΗ ΥΠΕΡ: Αποτελεσματική ρύθμιση της γλυκόζης ΚΑΤΑ: Παρεντερική χορήγηση Αύξηση ΣΒ Υπογλυκαιμίες

ΕΞΕΝΑΤΙΔΗ ΥΠΕΡ: Μείωση ΣΒ ΚΑΤΑ: Παρεντερική χορήγηση Γαστρεντερικές διαταραχές

ΘΕΡΑΠΕΙΑ Η ασθενής έλαβε βιλνταγλιτπίνη 50 mg Χ 2. Μετά από 6 μήνες είχε: FBG = 110 mg/dL, HbA1c = 6,8%, BMI = 31 Kg/m2. Δεν αναφέρει παρενέργειες από τη λήψη της αγωγής

ΠΕΡΙΓΡΑΦΗ 2ης ΠΕΡΙΠΤΩΣΗΣ ΠΕΡΙΓΡΑΦΗ 2ης ΠΕΡΙΠΤΩΣΗΣ Γυναίκα 60 ετών με διαβήτη από 2ετίας υπό μετφορμίνη 2000 mg/ημέρα. FBG = 150 mg/dL, HbA1c = 8,0%, ΣΒ = 99 Kg, BMI = 39 Kg/m2. Ιστορικό υπέρτασης. Η ασθενής έχει κάνει πολλές προσπάθειες αλλά δεν μπορεί να χάσει βάρος

ΕΠΟΜΕΝΟ ΒΗΜΑ?? Α. Γλιμεπιρίδη 4 mg/ημέρα Β. Ροσιγλιταζόνη 8 mg/ημέρα Δ. Βασική ινσουλίνη 10 U/βράδυ s.c Ε. Εξενατίδη 10 μg Χ 2 s.c

ΠΡΟΒΛΗΜΑ ΤΟ ΣΩΜΑΤΙΚΟ ΒΑΡΟΣ!!! ΑΓΩΓΗ: ΓΛΙΠΤΙΝΗ Η’ ΕΞΕΝΑΤΙΔΗ ΘΕΡΑΠΕΙΑ ΠΡΟΒΛΗΜΑ ΤΟ ΣΩΜΑΤΙΚΟ ΒΑΡΟΣ!!! ΑΓΩΓΗ: ΓΛΙΠΤΙΝΗ Η’ ΕΞΕΝΑΤΙΔΗ

ΘΕΡΑΠΕΙΑ Η ασθενής έλαβε βιλνταγλιπτίνη/μετφορμίνη 50/1000 mg Χ 2. Μετά από 6 μήνες είχε: FBG = 125 mg/dL, HbA1c = 7,0%, BMI = 38 Kg/m2. Δεν αναφέρει παρενέργειες από τη λήψη της αγωγής

ΠΕΡΙΓΡΑΦΗ 3ης ΠΕΡΙΠΤΩΣΗΣ ΠΕΡΙΓΡΑΦΗ 3ης ΠΕΡΙΠΤΩΣΗΣ Άνδρας 60 ετών με διαβήτη πρόσφατης διάγνωσης χωρίς αγωγή. FBG = 190 mg/dL, HbA1c = 9,5%, ΣΒ = 95 Kg, BMI = 37 Kg/m2. Ιστορικό εμφράγματος του μυοκαρδίου με ελαττωμένο κλάσμα εξώθησης (45%)

ΘΕΡΑΠΕΙΑ? Α. Μετφορμίνη 2000 mg/ημέρα + Γλιμεπιρίδη 4 mg/ημέρα Δ. Μετφορμίνη 2000 mg/ημέρα + Βασική ινσουλίνη 10 U/βράδυ s.c Ε. Μετφορμίνη 2000 mg/ημέρα + Εξενατίδη 10 μg Χ 2 s.c

ΣΟΥΛΦΟΝΥΛΟΥΡΙΑ + ΜΕΤΦΟΡΜΙΝΗ ΥΠΕΡ: Γρήγορη ρύθμιση της γλυκόζης ΚΑΤΑ: Υπογλυκαιμίες Αύξηση ΣΒ Αυξημένα καρδιαγγειακά συμβάματα???

ΓΛΙΤΑΖΟΝΗ + ΜΕΤΦΟΡΜΙΝΗ ΑΠΟΛΥΤΗ ΑΝΤΕΝΔΕΙΞΗ Η ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ

ΓΛΙΠΤΙΝΗ + ΜΕΤΦΟΡΜΙΝΗ ΥΠΕΡ: Όχι υπογλυκαιμία Διατήρηση του β-κυττάρου Όχι αύξηση ΣΒ ΚΑΤΑ: Δεν υπάρχουν δεδομένα για κλινικά συμβάματα

ΙΝΣΟΥΛΙΝΗ + ΜΕΤΦΟΡΜΙΝΗ ΥΠΕΡ: Αποτελεσματική ρύθμιση της γλυκόζης ΚΑΤΑ: Παρεντερική χορήγηση Αύξηση ΣΒ Υπογλυκαιμίες

ΕΞΕΝΑΤΙΔΗ + ΜΕΤΦΟΡΜΙΝΗ ΥΠΕΡ: Μείωση ΣΒ ΚΑΤΑ: Παρεντερική χορήγηση Γαστρεντερικές διαταραχές Δεν υπάρχουν δεδομένα για κλινικά συμβάματα

ΘΕΡΑΠΕΙΑ Ο ασθενής έλαβε βιλνταγλιπτίνη/μετφορμίνη 50/1000 mg Χ 2. Μετά από 6 μήνες είχε: FBG = 130 mg/dL, HbA1c = 7,1%, BMI = 36 Kg/m2. Δεν αναφέρει παρενέργειες από τη λήψη της αγωγής

ΠΕΡΙΓΡΑΦΗ 4ης ΠΕΡΙΠΤΩΣΗΣ ΠΕΡΙΓΡΑΦΗ 4ης ΠΕΡΙΠΤΩΣΗΣ Άνδρας 52 ετών με διαβήτη από 2ετίας. Αρχικά έλαβε μετφορμίνη 850 mg Χ 2 και στη συνέχεια προστέθηκε γλιμεπιρίδη 2 mg/ημέρα εξαιτίας HbA1c = 7,4%. Το ΣΒ αυξήθηκε κατά 3 Kg και τώρα έχει FBG = 90 mg/dL, HbA1c = 6,4%, ΣΒ = 93 Kg, BMI = 35 Kg/m2. Ο ασθενής αιτιάται συχνές συμπτωματικές υπογλυκαιμίες

ΘΕΡΑΠΕΙΑ? Α. Διακοπή γλιμεπιρίδης και προσθήκη πιογλιταζόνης 30 mg/ημέρα Β. Διακοπή γλιμεπιρίδης και προσθήκη βιλνταγλιπτίνης 50 mg Χ 2

ΜΕΤΦΟΡΜΙΝΗ + ΓΛΙΤΑΖΟΝΗ ΥΠΕΡ: Όχι υπογλυκαιμία Διατήρηση του β-κυττάρου ΚΑΤΑ: Αύξηση ΣΒ

ΜΕΤΦΟΡΜΙΝΗ + ΓΛΙΠΤΙΝΗ ΥΠΕΡ: Όχι υπογλυκαιμία Διατήρηση του β-κυττάρου Όχι αύξηση ΣΒ ΚΑΤΑ: ??

ΘΕΡΑΠΕΙΑ Ο ασθενής έλαβε βιλνταγλιπτίνη/μετφορμίνη 50/1000 mg Χ 2. Μετά από 6 μήνες είχε: FBG = 100 mg/dL, HbA1c = 6,6% και έχασε τα 3 Κg που είχε πάρει. Δεν αναφέρει παρενέργειες από τη λήψη της αγωγής

www.bpath.gr