Αςκενοκεντρικι προςζγγιςθ ςτθ διαχείριςθ αςκενϊν με Δ2. Ο ρόλοσ τθσ Βιλνταγλιπτίνθσ ςτο νζο κεραπευτικό αλγόρικμο Επιτυγχάνοντασ γλυκαιμικό ζλεγχο με εξατομίκευςθ τθσ κεραπείασ Π.Γ.ΧΑΛΒΑΤΣΙΩΤΗΣ Επίκ.Καθηγητής Β ΠΡΟΠΑΙΓΔΤΣΙΚΗ ΠΑΘΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΜΟΝΑΓΑ EΡΔΤΝΑ & ΓΙΑΒΗΣΟΛΟΓΙΚΟ ΚΔΝΣΡΟ ΠΑΝΔΠΙΣΗΜΙΟΤ ΑΘΗΝΩΝ ΠΑΝΔΠΙΣΗΜΙΑΚΟ ΓΔΝ.ΝΟΟΚΟΜΔΙΟ ΑΣΣΙΚΟΝ
Codex Hammurabi 17th and 21st centuries B.C Rates set for surgery, fractures, curing diseased muscles and other specific health care services. Fees set according to a sliding scale based on ability to pay. Spiegel et al, J Community Health. 1997 Feb; 22(1):69-89 Objective outcome measurement standards to assure quality of care. Outcomes information management to include data collection and evaluation. Consumer and patient's rights to be publicized, explained and made known to all. marketing and advertising activities promoted adoption of the plan.
Can you cure my diabetes doc! YES, we have now government approved guidelines (Roy Taylor, Newcastle UK)
Beyond Compliance Is Adherence Λιψθ φαρμάκων ςφμφωνα με τισ οδθγίεσ? Για ποιουσ λόγουσ παρεκκλίνουν των οδθγιϊν οι αςκενείσ? Η μθ ςυμμόρφωςθ μπορεί να επιβαρφνει επιπλζον το κόςτοσ?
ΕΠΙΛΟΓΕ ΘΕΡΑΠΕΙΑ ΑΙΣΙΑ ΤΝΕΠΕΙΕ ΜΗ ΤΜΜΟΡΦΩΗ 1. Τπογλυκαιμία 2. Αφξθςθ Β 3. Καρδιαγγειακόσ Κίνδυνοσ Hauber et al, Diabet Med 26:416-424, 2009
Αζθεμείς (%) Η πλειοψθφία των αςκενϊν δεν επιτυγχάνουν το ςτόχο τθσ ADA για HbA1c <7% 100 80 60 63% 7% GOAL Survey 12.4% 7.8% 37.2% > 8% 17.0% Μόμο ηο 7% ηωμ αζθεμώμ με διαβήηη ζηημ NHANES ηο 1999-2000 πέησταμ: HbA1c <7% Αρηηριακή πίεζη <130/80 mm Hg Σσμολική τοληζηερόλη <200 mg/dl 40 20 0 25.8% 37.0% HbA1c >10% > 9% > 8% 7%-8% < 7% Saydah SH et al. JAMA, 2004;291:335-342
Emergeny hospitalisations for Adverse Drug Reactions 2007 2009 Amongst population > 64 years Annual estimated ER visits 265.802 Emergency hospitalization 99.628 Budnitz et al. N Engl J Med 2011; 365:21.
Emergency Hospitalizations for Adverse Drug Effects in Older Americans
ACCORD All Cause Mortality & Primary Outcomes Event Curves Primary outcome (composite nonfatal MI, nonfatal stroke, CVD death) Mortality HR = 0.90 (95% CI = 0.78-1.04) p = 0.16 HR = 1.22 (95% CI =1.01-1.46) p = 0.04 standard intensive intensive standard
Θνητότητα σε 30 ημέρες (%) ΦΕΗ ΒΑΘΜΟΤ ΓΛΤΚΑΙΜΙΑ & ΘΝΗΣΟΣΗΣΑ ΜΕΣΑ ΑΠΟ ΕΜΥΡΑΓΜΑ ΜΤΟΚΑΡΔΙΟΤ 25 22.6% *Σε θρομβόλυση 20 15 10 5 0 P<0.001 8.0% 4.3% 3.2% 2.5% < 81 81-99 100-125 126-150 151-199 >199 n=62 n=123 n=280 n=186 n=200 n=196 άκχαρο αίματοσ (mg/dl) 8.7% Pinto DS, et al. J Am Coll Cardiol. 2005;1:178-83.
δραςτθριότθτα των ινκρετινϊν T2ΣΓ Insulin Glucose Μειωμένη απάνηηζη ινκπεηινών Μείωζη λειηοςπγικόηηηαρ νηζιδίων Υπεπγλςκαιμία Glucagon Αναζηολή DPP-4 Insulin Glucose Δνίζτσζη δράζης ινκρεηινών Βεληίωζη λειηοσργικόηηηας νηζιδίων Βεληίωζη γλςκαιμίαρ Glucagon 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.
Mean HbA1c (%) Vildagliptin vs Gimepiride ςε ςυνδυαςμό με Metformin: ΗbA1c ςε 1 ζτοσ Add-on Treatment to Metformin (~1.9 g Mean Daily) Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin 0.4% 0.5% NI: 97.5% CI (0.02, 0.16) CI=confidence interval; HbA1c=hemoglobin A1c; NI=not inferior Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157 166. Time (weeks)
Body Weight (kg) Vildagliptin vs Gimepiride ΑΤΞΗΗ Β Add-on Treatment to Metformin (~1.9 g Mean Daily) 1.8 kg difference Time (weeks) Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393). Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157 166. Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin
Incidence (%) No. of Events No. of Events Vildagliptin vs Gimepiride ΤΠΟΓΛΤΚΑΙΜΙΑ Αςκενείσ με >1 Επειςόδιο (%) Επειςόδια υπογλυκαιμίασ Βαρειά επειςόδια n = 1389 1383 1389 1383 1389 1383 Safety population. Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157 166. Vildagliptin 50 mg twice daily + metformin Glimepiride up to 6 mg once daily + metformin
Glucagon (pmol/l) GLP-1 (pmol/l) Glucose (mmol/l) (pmol/l min -1 m -2 mm) Effects of Vildagliptin Monotherapy: in IGT Population a 12.0 GLP-1 Vildagliptin 50 mg once daily (n=89) Placebo (n=89) b 9.0 Glucose 8.0 Meal 8.0 Meal 4.0 7.0 c ISR AUC 0-2h / Glucose AUC 0-2h 0.0 8.0 6.0 4.0 2.0 0.0 2.0 4.0 30 0 30 60 90 120 Time (min) β-cell Function * Insulin secretion relative to glucose Vildagliptin 50 mg once daily (n=89) Placebo (n=89) Intention-to-treat population. *P=0.002 vs placebo. Rosenstock J, et al. Diabetes Care. 2008: 31: 30 35. d 6.0 30 0 30 60 90 120 Time (min) 26 24 22 20 18 Glucagon Meal 30 0 30 60 90 120 Time (min)
Mean Change in HbA1c (%) Vildagliptin & Metformin: ΒΑΘΜΟ ΤΠΕΡΓΛΤΚΑΙΜΙΑ Overall* Τποομάδεσ με HbA1c a >8% >9% 10% >11% BL mean = ~8.7% ~9.2% ~9.9% ~10. 6% ~12. 1% n = 285 201 96 35 86 * * High-dose vilda + met (50/1000 mg twice daily) c BL=baseline; EP=end point; HbA1c=hemoglobin A1c; met=metformin; vilda=vildagliptin *P <0.001 vs BL; **P <0.001 vs monotherapy components; 100 mg once daily is not an approved dose. Intention-to-treat population. a Raw mean change from baseline; b Least-square mean change from baseline. Bosi E, et al. Diabetes Obes Metab (in press); Data on file, Novartis Pharmaceuticals, c LMF237A2302 and d LMF237A2302S1. Vilda 100 mg daily + met 2000 mg daily open-label sub-study (P <0.001 vs BL) d *
Ουδεμία δράςθ ςτα επίπεδα γλυκόηθσ μθ διαβθτικϊν Insulin (μu/ml) Glucose (mg/dl) 100 75 g glucose Dose 400 75 g glucose Dose 75 300 50 200 25 100 0 90 60 30 0 30 60 90 120 150 180 210 240 270 300 Time (min) 0 90 60 30 0 30 60 90 120 150 180 210 240 270 300 Time (min) T2DM, placebo T2DM, vildagliptin Healthy individuals, placebo Healthy individuals, vildagliptin El-Ouaghlidi A, et al. J Clin Endocrinol Metab. 2007; 92: 4165 4171.
Change in HbA1c (%) from baseline Vildagliptin: low risk for hypoglycaemia during Ramadan 1 A study on 12,243 Muslims showed 7.5-fold increased risk of severe hypoglycaemia during Ramadan 2 0.1 0.0-0.2 Vildagliptin 50 mg twice daily (n=23) Sulfonylurea (n=36) -0.4 Hypoglycemic events Vildagliptin Sulfonylurea Any events 0 34 (in 15 pts) Severe events 0 1 1 Hassanein M, et al. Curr Med Res Opin 2011; 27: 1367 1374; 2 Al-Arouj M, et al. Diabetes Care 2010; 33: 1895 1902
VILDAGLIPTIN + METFORMIN Vs GLITAZONES + METFORMIN
Vildagliptin vs Rosiglitazone 9.5 9 8.5 Mean HbA1c (%) b Edema Incidence (%) c 8 7.5 7 6.5 Not NI* 12 10 6 5.5 0 4 12 16 24 32 40 52 64 76 88 104 100 Mean Body Weight (kg) b 98 96 94 8 6 4 2 92 90 88 4.7, P <0.001** 0 104 weeks 86 0 4 12 16 24 32 40 52 64 76 88 104 Vildagliptin 50 mg twice daily Rosiglitazone 8 mg once daily Time (Weeks) *Not non-inferior; **Statistically significant larger increase in body weight from baseline to end point was seen in the rosiglitazone group than in the vildagliptin group; P <0.001. a Head-to-head vildagliptin vs rosiglitazone comparison: 80-week extension to 24-week core study; extension intention-to-treat population; b Vildagliptin n=354, rosiglitazone n=179; observations censored at rescue med; error bars represent standard error values; c Pitting edema, peripheral edema, and other edema. Rosenstock J, et al. Diabetes Obes Metab. 2009; 11: 571 578. Data on file, Novartis Pharmaceuticals. LAF237A2354.
Mean HbA1c (%) Vildagliptin Add-on to Pioglitazone Add-on Treatment to Pioglitazone 45 mg Daily 9.0 8.8 8.6 Vildagliptin 50 mg once daily + pioglitazone (n=124) Vildagliptin 50 mg twice daily + pioglitazone (n=136) Placebo + pioglitazone 45 mg daily (n=138) 8.4 8.2 8.0 7.8 7.6 7.4 4 0 4 8 12 16 20 24 Garber A, et al. Diabetes Obes Metab. 2007; 9: 166 174. Time (weeks) * * 0.5% vs placebo 0.7% vs placebo
Peripheral Edema (%) Peripheral Edema (%) Vildagliptin - Pioglitazone: Λιγότερα Οιδιματα 10 8 9.3 Vildagliptin 100 mg once daily Pioglitazone 30 mg once daily Vildagliptin 50 mg once daily + pioglitazone 15 mg once daily Vildagliptin 100 mg once daily + pioglitazone 30 mg once daily 6 5.2 6.1 4 3.5 2 0 Vildagliptin 100 mg once daily (n=154); pioglitazone 30 mg once daily (n=161); vildagliptin 50 mg once daily + pioglitazone 15 mg daily (n=144); vildagliptin 100 mg once daily + pioglitazone 30 mg daily (n=148). Intention-to-treat population, low-dose combination arm is not included. 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.
ΙΝΟΤΛΙΝΟΘΕΡΑΠΕΙΑ
Μζςθ HbA 1c (%) Προςκικθ Vildagliptin ςε αςκενείσ με διαβιτθ τφπου 2 που ελζγχονταν ανεπαρκϊσ με ινςουλίνθ 9.0 Εικονικό φάρμακο + ινςουλίνθ Vildagliptin 50 mg QD + ινςουλίνθ Vildagliptin 50 mg BID + ινςουλίνθ (βαςικι + επζκταςθ) 8.5 Αλλαγι από Εικ. Φάρμακο + Ινςουλίνθ ςε Vildagliptin + Ινςουλίνθ 8.0 7.5-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Χρόνοσ (εβδομάδεσ) Fonseca V, et al. Diabetologia published on line March 27, 2007
Λιγότερα υπογλυκαιμικά επειςόδια με τθν προςκικθ Vildagliptin ςε ινςουλίνθ Αριθμός αζθενών Αριθμός επειζοδίων Αρ. ζοβαρών επειζοδίων Vildagliptin + ινςουλίνθ Εικ. Φάρμακο + ινςουλίνθ 50 200 40 45 160 185 10 8 30 20 33 120 80 113 6 4 6 10 40 2 0 0 0 0 Σοβαπά, βαθμού 2 επειζόδια: Κανένα με ηην πποζθήκη vildagliptin ζε ινζοςλίνη, ένανηι έξι επειζοδίων με ηην πποζθήκη εικονικού θαπμάκος ζε ινζοςλίνη (P<0,01). 26 Fonseca V, et al. Diabetologia, published on line March 27, 2007.
VILDAGLIPTIN & ΤΠΟΓΛΤΚΑΙΜΙΑ ΑΠΑΝΣΗΗ ΣΗΝ ΤΠΟΓΛΤΚΑΙΜΙΑ Placebo vilda Glucagon 33,9 + 6,7 46,7 + 6,9 0,039 28 pt on Vildagliptin for 4 w Double-blind, crossover study Ahren et al 2009, J Clin Endocrinol Metab 94:1236-43
«ΣΡΙΣΗ ΗΛΙΚΙΑ»
ΝΕΦΡΙΚΗ ΑΝΕΠΑΡΚΕΙΑ
Patients with Moderate or Severe Renal Impairment
Adjusted Mean Change from Baseline in HbA1c (%) Adjusted Mean Change from Baseline in HbA1c (%) Patients with Moderate or Severe Renal Impairment Moderate RI Severe RI N= 157 128 BL= 7.86 7.79 N= 122 95 BL= 7.69 7.65 * * Vildagliptin 50 mg qd Placebo Lukashevich V et al. Diabetes Obes Metab 2011; 13: 947
GHbA1c PPG
Β-Κφτταρο
β ΚΤΣΣΑΡΟ & ΙΝΟΤΛΙΝΟΑΝΣΙΣΑΗ
Butler et al, 2003 Diabetes 52:102-110 ΝΗΙΔΙΑ-ΠΑΧΤΑΡΚΙΑ-ΔΙΑΒΗΣΗ
BrdU-positive Cells (%) ApopTag -positive Cells (%) -cell Mass (mg) Vildagliptin: Αφξθςθ μάηασ β-κυττάρων (Πειραματικό πρότυπο νεογνικισ παγκρεατικισ ανάπτυξθσ επίμυοσ) Insulin Vehicle Vildagliptin 60 mg/kg 21 days Αναγζννθςθ Απόπτωςθ Μάηα -κυττάρων 120 100 80 60 40 20 0 Vehicle P <0.001 Vildagliptin 2.5 2.0 1.5 1.0 0.5 0.0 Vehicle P <0.05 Vildagliptin 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Vehicle P <0.05 Vildagliptin ΗΜΕΡΑ 7 ΗΜΕΡΑ 21 Duttaroy A, et al. Diabetes. 2005; 54 (Suppl 1): A141. Abstract 572-P and poster presented at ADA.
Vildagliptin & b-cell Function After a Euglycemic Hyperinsulinemic and Hyperglycemic Clamp Derosa et al DIABETES TECHNOLOGY & THERAPEUTICS Vol 14, No 6, 2012
ΑΦΑΛΕΙΑ
Vildagliptin & hepatic enzyme elevations 38 Phase II and Phase III clinical trials as monotherapy or in combination with met, TZDs, (SUs) or insulin for 12 weeks up to>104 weeks completed as of 5/2009 Ligueros-Saylan M, et al. DOM 2010 in press
Vildagliptin & pancreatitis infection skin lesions PANCREATITIS - INFECTION SKIN RELATED 38 Phase II and Phase III clinical trials as monotherapy or in combination with met, TZDs, (SUs) or insulin for 12 weeks up to>104 weeks completed as of 5/2009 Ligueros-Saylan M, et al. DOM 2010 in press
ΘΝΗΙΜΟΣΗΣΑ ΑΠΟ ΣΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ
Change from BL (mmhg) EUCREAS: ΑΠ ςε υπζρταςθ (ΑΠ >140 mmhg & ΔΑΠ >90 mmhg) DBP SBP n = 57 59 57 59 * * Vildagliptin 50 mg twice daily + metformin Placebo + metformin Bosi E, et al. Presented at ADA Annual Meeting; June 22 26, 2007; Chicago, IL. 2165-PO. *
Change from BL (%) EUCREAS : ΛΙΠΙΔΙΑ ΝΗΣΕΙΑ Add-on Treatment to Metformin (2.1 g Mean Daily) TG TC LDL-C HDL-C Vildagliptin 50 mg once daily + metformin (n=142) Vildagliptin 50 mg twice daily + metformin (n=141) Placebo (n=128) * Bosi E, et al. Diabetes Care. 2007; 30; 890 895.
ΔΙΑΚΤΜΑΝΕΙ ΑΚΧΑΡΟΤ & ΑΓΓΕΙΑ
R. Marfella et al. / Journal of Diabetes and Its Complications 2009 Article in press 48
ΔΙΑΣΡΟΦΗ & ΑΚΗΗ